Radionuclide Generators. New Systems for Nuclear Medicine Applications 9780841208223, 9780841210691

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Radionuclide Generators. New Systems for Nuclear Medicine Applications
 9780841208223, 9780841210691

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Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.fw001

Radionuclide Generators

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.fw001

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

ACS

SYMPOSIUM

SERIES

Radionuclide Generators

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.fw001

New Systems for Nuclear Medicine Applications Furn F. Knapp, Jr., E D I T O R Thomas A . Butler, E D I T O R Oak Ridge National

Laboratory

Based on a symposium sponsored by the Division of Nuclear Chemistry and Technology at the 185th Meeting of the American Chemical Society, Seattle, Washington, M a r c h 20-25, 1983

American Chemical Society, Washington, D.C. 1984

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

241

Library of Congress Cataloging in Publication Data Radionuclide

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.fw001

(ACS

generators.

s y m p o s i u m series, ISSN 0 0 9 7 6156: 241)

" B a s e d on a s y m p o s i u m s p o n s o r e d b y the Division N u c l e a r C h e m i s t r y a n d T e c h n o l o g y at the 185th M e e t i n g o f the American C h e m i c a l S o c i e t y , S e a t t l e , W a s h i n g t o n , March 2 0 - 2 5 , 1983."

of

1. N u c l e a r m e d i c i n e — C o n g r e s s e s . 2. R a d i o n u c l i d e g e n e r a t o r s — C o n g r e s s e s . I. Knapp, F. F., 1944 II. B u t l e r , T h o m a s A . ( T h o m a s Arthur), 1919 III. American C h e m i c a l S o c i e t y . Division o f N u c l e a r C h e m i s t r y a n d T e c h n o l o g y . I V . American C h e m i c a l S o c i e t y M e e t i n g (185th: 1983: S e a t t l e , W a s h . ) V. Series. [DNl.M: 1. Radionuclide generators— I n s t r u m e n t a t i o n — C o n g r e s s e s . 2. R a d i o i s o t o p e s — C o n g r e s s e s . WN 150] R895.A2R33 1984 ISBN 0-8412- 0 8 2 2-0

616.07 57

83 25875

C o p y r i g h t © 1984 American

C h e m i c a l Society

All R i g h t s R e s e r v e d . T h e a p p e a r a n c e o f the c o d e at the b o t t o m o f the first page o f e a c h c h a p t e r i n t h i s v o l u m e i n d i c a t e s the c o p y r i g h t o w n e r ' s c o n s e n t t h a t r e p r o g r a p h i c c o p i e s o f the c h a p t e r m a y be m a d e f o r p e r s o n a l o r i n t e r n a l use o r f o r the p e r s o n a l o r i n t e r n a l use o f specific c l i e n t s . T h i s c o n s e n t is g i v e n o n the condition, h o w e v e r , that the c o p i e r p a y the stated per c o p y fee t h r o u g h the C o p y r i g h t C l e a r a n c e C e n t e r , Inc. f o r c o p y i n g b e y o n d that p e r m i t t e d b y S e c t i o n s 107 o r 108 o f the U . S . C o p y r i g h t L a w . T h i s c o n s e n t d o e s not e x t e n d to c o p y i n g o r t r a n s m i s s i o n b y a n y m e a n s — g r a p h i c o r e l e c t r o n i c — f o r a n y o t h e r p u r p o s e , s u c h as f o r g e n e r a l distribution, f o r a d v e r t i s i n g o r p r o m o t i o n a l p u r p o s e s , f o r c r e a t i n g a new c o l l e c t i v e w o r k , f o r resale, o r f o r i n f o r m a t i o n s t o r a g e a n d r e t r i e v a l systems. T h e c o p y i n g fee f o r e a c h c h a p t e r is i n d i c a t e d i n the c o d e at the bottom o f the first page o f the c h a p t e r . T h e c i t a t i o n o f t r a d e n a m e s a n d / o r n a m e s o f m a n u f a c t u r e r s i n t h i s p u b l i c a t i o n is not to be c o n s t r u e d as a n e n d o r s e m e n t o r as a p p r o v a l b y ACS o f the c o m m e r c i a l p r o d u c t s o r services referenced h e r e i n ; n o r s h o u l d the m e r e reference h e r e i n to a n y d r a w i n g , s p e c i f i c a t i o n , c h e m i c a l process, o r o t h e r d a t a be r e g a r d e d as a license o r as a c o n v e y a n c e o f a n y r i g h t o r p e r m i s s i o n , to the h o l d e r , reader, o r a n y o t h e r p e r s o n o r corporation, t o m a n u f a c t u r e , r e p r o d u c e , use, o r sell a n y p a t e n t e d i n v e n t i o n o r c o p y r i g h t e d w o r k that m a y i n a n y w a y be r e l a t e d t h e r e t o . R e g i s t e r e d n a m e s , t r a d e m a r k s , etc., used i n this p u b l i c a t i o n , even w i t h o u t s p e c i f i c i n d i c a t i o n t h e r e o f , a r e not t o be c o n s i d e r e d u n p r o t e c t e d b y l a w . PRINTED IN THE UNITED STATES OF AMERICA

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

ACS Symposium Series

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.fw001

M . Joan Comstock, Series Editor Advisory Board Robert Baker

Geoffrey D. Parfitt

U.S. Geological Survey

Carnegie Mellon University

Martin L. Gorbaty

Theodore Provder

Exxon Research and Engineering C o .

Glidden Coatings and Resins

Herbert D. Kaesz

James C. Randall

University of California- Los Angeles

Phillips Petroleum Company

Rudolph J. Marcus

Charles N. Satterfield

Office of Naval Research

Massachusetts Institute of Technology

Marvin Margoshes

Dennis Schuetzle

Technicon Instruments Corporation

Ford Motor Company Research Laboratory

Donald E. Moreland U S D A , Agricultural Research Service

Davis L. Temple, Jr. Mead Johnson

W. H. Norton J. T. Baker Chemical Company

Charles S. Tuesday General Motors Research Laboratory

Robert Ory U S D A , Southern Regional Research Center

C. Grant Willson IBM Research Department

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.fw001

FOREWORD The ACS SYMPOSIUM S E R I E S was founded in 1 9 7 4 to provide a medium for publishing symposia quickly in book form. The format of the Series parallels that of the continuing A D V A N C E S I N C H E M I S T R Y S E R I E S except that i n order to save time the papers are not typeset but are reproduced as they are submitted by the authors i n camera-ready form. Papers are reviewed under the supervision of the Editors with the assistance of the Series Advisory Board and are selected to maintain the integrity of the symposia; however, verbatim reproductions of previously published papers are not accepted. Both reviews and reports of research are acceptable since symposia may embrace both types of presentation.

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

PREFACE

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.pr001

THE

D E V E L O P M E N T O F C L I N I C A L R A D I O N U C L I D E G E N E R A T O R S has

been a

significant factor contributing to the rapid growth of nuclear medicine practice. Technetium-99m obtained from the Mo-99/Tc-99m generator system is the most widely used radionuclide for in vivo diagnostic tests. T h e purpose of the s y m p o s i u m o n new radionuclide generator systems for nuclear medicine was to review the state of development of new radionuclide generator systems for application in both diagnostic and therapeutic nuclear medicine. The p r o g r a m was broadly divided into three sessions o n shortlived radionuclides, positron-emitting radionuclides, and radionuclide p r o duction and miscellaneous applications. Interest in new generator-derived single photon-emitting radionuclides has increased in recent years due in part to advances in " f a s t " g a m m a cameras that allow very high count rates and computerized image reconstruction techniques. In a d d i t i o n , use of short-lived radionuclides such as A u - 1 9 5 m (30.5 sec), Ir-191m (5 sec), Kr-81 (13.3 sec), and Ta-178 (9.3 min) for radionuclide angiography allows repeat studies at short intervals w i t h significant reduction in absorbed radiation dose; thus, therapeutic intervention can be assessed. T h i s is particularly important in pediatric applications, such as the evaluation of intracardiac shunts in children with Ir-19Im. T h e wide availability of positron emission tomographic instrumentation has stimulated the use of generator-derived positron-emitting radionuclides such as R b - 8 2 , M n - 5 2 m , and Ga-68. T h e availability of these generatorderived radionuclides is very important for positron tomography studies and now allows use of the procedure at facilities w h i c h are remote f r o m production sites. The on-site cyclotron is no longer essential for patient e x a m i n a t i o n by positron tomography. Radionuclides with therapeutic a p p l i cations, such as the a l p h a emitter Bi-212, can also be obtained f r o m radionuclide generators and are of interest for attachment to tissue-specific m o n o c l o n a l antibodies. A l l of the above radionuclides obtained from generator systems were discussed in this s y m p o s i u m . T h e s y m p o s i u m offered a g o o d opportunity to review and discuss in detail the new generation and improved versions o f older radionuclide generators that are being developed for nuclear medicine applications. O u r goal at this s y m p o s i u m was to emphasize the chemical and mechanical aspects of generator design and performance. We were pleased to have representatives from the private sector participate a n d describe a d ix

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.pr001

varices i n radionuclide generator systems that w i l l be commercially available to provide the medical c o m m u n i t y a ready access to important new diagnos­ tic aids. T h e chapters i n this v o l u m e also review the clinical applications o f these generators to provide a comprehensive overview o f generator design, development, a n d use. We felt there was a real need f o r a b o o k describing the recent developments i n radionuclide generators. T h i s b o o k w i l l be o f interest to basic researchers, clinicians, technicians, and other professionals w o r k i n g in the nuclear medicine area. We w o u l d like to express o u r thanks to a l l o f o u r colleagues w h o participated i n this s y m p o s i u m , including T h o m a s F . Budinger w h o took time f r o m his busy schedule to present the keynote address. We also thank L i n d a A i l e y for her enthusiasm a n d help i n c o o r d i n a t i n g the manuscript correspondence a n d those w h o reviewed the manuscripts to help make this important volume available to the scientific c o m m u n i t y . F U R N F. K N A P P , T H O M A S A.

JR.

BUTLER

Oak Ridge National Laboratory Oak Ridge, Tennessee August 1983

χ

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

1 A New Generator for Production of Short-Lived Au-195m Radioisotope K.

J.

PANEK,

J.

LINDEYER,

and

H.

C.

VAN

DER

VLUGT

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch001

B y k - M a l l i n c k r o d t CIL B . V . , C y c l o t r o n & Isotope Laboratories, P.O. B o x 3, 1755 ZG Petten, H o l l a n d

A g e n e r a t o r has been d e v e l o p e d t o p r o d u c e multimillicurie amounts o f 30.6 s e c o n d Au-195m. Gold-195m, a d a u g h t e r isotope o f 41.6 h o u r Hg-195m, is eluted a s neutral and sterile sodium thiosulphatoaurate (I) c o m p l e x , and a s s u c h , is indicated for dynamic studies in cardiology. Mercury-195m is p r o d u c e d by irradiation o f g o l d targets w i t h 28 MeV protons, yielding by t h e (p,3n) nuclear reaction Hg-195m and Hg-195 ( 9 . 9 h o u r s ) a t rates o f 4.6 and 12 mCi/μAh, respectively. M e r c u r y is s e p a r a t e d f r o m irradiated g o l d by distillation and collection in nitric acid. This solution is neutralized and l o a d e d on a column o f silica g e l modified with metallic sulphide. Columns a r e eluted a t 3-5 m i n u t e intervals with a solution containing 29.8 mg/ml s o d i u m thiosulphate, p e n t a h y d r a t e and 10 mg/ml s o d i u m nitrate. Yields o f Au-195m v a r y between 24-45% o f t h e o r y , d e p e n d i n g on t h e total Hg activity and t h e g e n e r a t o r production method. Gold-195m is o b t a i n e d in 3-4 s e c o n d s by eluting with 2 ml u n d e r p r e s s u r e . C o n t a m i ­ nation o f t h e eluate with m e r c u r y isotopes d e c r e a s e s after a b o u t 20 elutions t o 0.4 - 0.8 μCi Hg-195m/ mCi Au-195m.

A l t h o u g h t h e 0 s - 1 9 1 / I r - 1 9 1 m s y s t e m i s one o f t h e p o t e n t i a l l y interesting generators f o r the u l t r a s h o r t - l i v e d radionuclides (USLR) and was d e s c r i b e d by C a m p b e l l and N e l s o n ( 1 ) as e a r l y as i n 1956, i t was o n l y t h e g r o w i n g i n t e r e s t f o r a p p l i c a t i o n o f USLR i n c a r d i o l o g y , that stimulated a broader research i n t h i s f i e l d . As a r e s u l t , a number o f g e n e r a t o r s l i k e Cd-109/Ag-109m ( 2 ) , 0 s - 1 9 1 / I r - 1 9 1 m ( 2 , 3 ) , Rb-81/Kr-81m ( 4 ) , Br-77/Se-77m ( 5 ) , W-178/Ta-178 (6) have been s t u d i e d i n t h e l a s t y e a r s . The Hg-195m/Au-195m g e n e r a t o r was t h e o r e t i c a l l y c o n s i d e r e d by L e b o w i t z (7_) and e x p e r i m e n t a l l y s t u d i e d by Yano (0), apparently

0097-6156/ 84/ 0241 -0003506.00/ 0 © 1984 American Chemical Society

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

4

RADIONUCLIDE GENERATORS

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch001

w i t h o u t s u c c e s s f u l c o n c l u s i o n . From t h e p u b l i s h e d d a t a on t h e e x i s t i n g g e n e r a t o r s y s t e m s , i t was however s e e n , t h a t none o f t h e USLR o b t a i n e d from t h e s e g e n e r a t o r s was optimum f o r t h e i n t e n d e d a p p l i c a t i o n i n c a r d i o l o g y ( T a b l e I ) . I n a d d i t i o n , none o f t h e g e n e r a t o r s y s t e m s ( e x c e p t f o r Kr-81m) worked e f f i c i e n t l y and e c o n o m i c a l l y and none were s u i t a b l e f o r l a r g e r s c a l e o r commerc i a l production. E v a l u a t i n g t h e a d v a n t a g e s and d i s a d v a n t a g e s o f t h e t h r e e p o t e n t i a l l y most p r o m i s i n g c a n d i d a t e s f o r USLR g e n e r a t o r s , i . e . Cd-109/Ag-109m, 0 s - 1 9 1 / I r - 1 9 1 m and Hg-195m/Au-195m ( T a b l e I I ) , we came t o t h e c o n c l u s i o n t h a t t h e l a t t e r p a r e n t - d a u g h t e r p a i r r e p r e s e n t s the b e s t p o s s i b l e compromise.

Table I .

Generators

Parent Isotope

f o r USLR - S p e c i f i c a t i o n o f

Isotopes

: lh l o n g enough f o r t r a n s p o r t a t i o n Photon energy not too h i g h , p e r m i t t i n g effective shielding H i g h decay y i e l d t o d a u g h t e r i s o t o p e

D a u g h t e r I s o t o p e : 1h o p t i m a l l y c a 20 s e c . P h o t o n e n e r g y between 80 - 250 keV High photon e m i s s i o n y i e l d C h e m i c a l form t h a t s t a y s i n t h e c i r c u l a t i o n

Table I I .

P o t e n t i a l c a n d i d a t e s f o r USLR

Generators

Advantage

Disadvantage

0s-191/Ir-191m

Jh P a r e n t Reactor i s o t o p e Photon energy daughter

Parent beta e m i t t e r L o a d i n g mg q u a n t i t i e s per generator 1H d a u g h t e r t o o s h o r t Low p h o t o n y i e l d Iridium chemistry

Cd-109/Ag-109m

Ik D a u g h t e r Photon energy

T% P a r e n t t o o l o n g Low p r o d u c t i o n r a t e Low p h o t o n y i e l d

Hg-195m/Au-195m

daughter

lh D a u g h t e r High photon y i e l d Acceptable production rate C a r r i e r free parent isotope

Ik

P a r e n t somewhat s h o r t

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch001

1.

PANEK ET AL.

Short-Lived

Au-195m

Radioisotope

5

Theoretical considerations. By t h e n a t u r e o f t h e i n t e n d e d a p p l i c a t i o n o f Au-195m, r e q u i r i n g d i r e c t l i n k i n g o f t h e g e n e r a t o r t o t h e p a t i e n t , i t was o b v i o u s t h a t t h e s e p a r a t i o n s y s t e m and gener a t o r d e s i g n must p o s s e s s a number o f s p e c i f i c f e a t u r e s , a s f o r i n s t a n c e g i v e n i n T a b l e I I I . These r e q u i r e m e n t s had a d i r e c t t e c h n i c a l c o n s e q u e n c e s f o r t h e s e p a r a t i o n c h e m i s t r y and s e l e c t i o n o f m a t e r i a l s f o r the generator c o n s t r u c t i o n . For i n s t a n c e , a s m a l l c o l u m n c o n t a i n i n g m i n i m a l bed m a t e r i a l w o u l d l i m i t t h e maximum amount o f p a r e n t i s o t o p e t h a t c o u l d be l o a d e d t o o n l y a few milligrams. Inorganic sorbents, preferable for t h e i r r a d i a t i o n s t a b i l i t y , u s u a l l y have l o w e r a d s o r p t i o n c a p a c i t y and m i g h t even r e q u i r e l o a d i n g w i t h c a r r i e r - f r e e p a r e n t i s o t o p e . A s h o r t column bed t o g e t h e r w i t h t h e e x p e c t e d l a r g e number o f s u c c e s s i v e e l u t i o n s w o u l d r e q u i r e e x t r e m e l y good f i x a t i o n o f t h e p a r e n t i s o t o p e t o t h e c o l u m n bed t o make i t v i r t u a l l y non e l u t a b l e . To d e s i g n a p u r p o s e f u l , y e t n o t t o o e x c e s s i v e e x p e r i m e n t a l scheme, we d e c i d e d t o f o c u s o u r r e s e a r c h on i n o r g a n i c s o r b e n t s . To a c q u i r e i n a s h o r t t i m e a s much i n f o r m a t i o n a s p o s s i b l e , we f u r t h e r d e c i d e d t o d i v i d e the problem of the generator ( a d s o r p t i o n o f the parent i s o t o p e and e l u t i o n o f d a u g h t e r ) , and t o i n v e s t i g a t e t h e a d s o r p t i o n o f m e r c u r y and g o l d s e p a r a t e l y . S i n c e we e x p e c t e d t h a t f o r e a c h p a r t i c u l a r s o r b e n t a " m a t c h i n g " e l u e n t w o u l d have t o be f o u n d , t h e above m e n t i o n e d d i v i s i o n o f t h e a d s o r p t i o n - e l u t i o n p r o b l e m made i t p o s s i b l e t o s c r e e n r a p i d l y ( i n b a t c h a d s o r p t i o n e x p e r i m e n t s ) a l a r g e number o f s o r b e n t - e l u e n t c o m b i n a t i o n s , w h i c h w o u l d be o t h e r w i s e i m p o s s i b l e t o t e s t i n c o l u m n e x p e r i m e n t s . B e c a u s e o f t h e v a s t v a r i e t y o f known s o r b e n t s u s e a b l e f o r a d s o r p t i o n o f m e r c u r y , i t was c l e a r t h a t t h e s c r e e n i n g e x p e r i m e n t s c o u l d n o t be e x h a u s t i v e , b u t s h o u l d be a t l e a s t r e p r e s e n t a t i v e f o r the p o t e n t i a l l y u s e f u l groups of sorbents w i t h r e l a t e d p r o p e r t i e s . Thus we i n c l u d e d s o r b e n t s f r o m t h e g r o u p o f h y d r a t e d o x i d e s s i l i c a g e l , h y d r a t e d manganese d i o x i d e (HMDO), h y d r a t e d z i r c o n i u m o x i d e and a l u m i n a , p h o s p h a t e s ( z i r c o n i u m p h o s p h a t e ) and as a g e n e r a l l y u s e f u l s o r b e n t c h a r c o a l was a l s o a d d e d . To e x p l o i t t h e a f f i n i t y o f m e r c u r y t o s u l p h u r and i t s compounds, s o r b e n t s c o n t a i n i n g e l e m e n t a l s u l p h u r and m e t a l l i c s u l p h i d e s ( s i l v e r s u l p h i d e and z i n c s u l p h i d e ) were a l s o i n c l u d e d . To t e s t a t l e a s t some o f t h e r e c e n t l y d e v e l o p e d , and p o t e n t i a l l y v e r y u s e f u l s o r b e n t s f r o m t h e g r o u p o f a n c h o r e d c h e l a t e s , two r e p r e s e n t a t i v e s o r b e n t s were c h o s e n , s i l i c a g e l w i t h c h e m i c a l l y bonded m e r c a p t o p r o p y l g r o u p s ( S i O ^ - S H ) , w h i c h e x p l o i t s t h e a f f i n i t y t o s u l p h u r , and s i l i c a g e l w i t h c h e m i c a l l y bonded a m i n o p r o p y l g r o u p s ( S i C ^ - N r ^ ) , e x p l o i t i n g t h e a f f i n i t y o f m e r c u r y t o a m i n e s . As a l a s t g r o u p we t e s t e d s o r b e n t s c o a t e d w i t h m e t a l s . These were r e p r e s e n t e d by Ag c o a t e d S i C L and Au c o a t e d S i O ^ . S i n c e some o f t h e s e l e c t e d m a t e r i a l s ( s u l p h u r , z i n c s u l p h i d e , e t c ) were n o t m e c h a n i c a l l y s u i t a b l e ( f i n e p o w d e r s ) i t was d e c i d e d t o use s u c h m a t e r i a l s i n a f o r m of modified sorbents, i . e . mechanically s u i t a b l e c a r r i e r material ( s i l i c a g e l ) coated with the a c t i v e sorbent i n q u e s t i o n .

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

6

RADIONUCLIDE

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch001

Table I I I .

GENERATORS

S p e c i f i c a t i o n s o f S e p a r a t i o n System f o r USLR

Sorbent

:

Material stable against radiation, preferably inorganic Nontoxic Insoluble Good m e c h a n i c a l p r o p e r t i e s Good p a c k i n g and flou/ c h a r a c t e r i s t i c s (of the column) Easy t o p r e p a r e and h a n d l e Very s t r o n g b i n d i n g o f p a r e n t i s o t o p e , preferably total immobilization

Eluent

:

N o n r e a c t i v e towards adsorbed p a r e n t i s o t o p e Rapidly r e a c t i n g w i t h daughter i s o t o p e C o n v e r t i n g daughter i s o t o p e to chemical form n o n r e a c t i v e t o s o r b e n t Nontoxic P h y s i o l o g i c a l pH Isotonic Chemically stable

Eluate

:

O b t a i n e d i n l o w volume 20 mins) both sepharose and CPG lipoamide columns have a s i m i l a r tendency: that i s , the amount of Hg-195m i n s o l u t i o n b u i l d s up as shown i n Table V. Conversely, t h i s l e v e l decreases to very low values with repeated use. Another point worth noting i s the b u i l d up of the r a d i o a c t i v e Au-195 with

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

3.

BETT ET AL.

First- Pass A

Table V:

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch003

Lipoamide (successive elutions)

45

V a r i a t i o n of Hg-195m Breakthrough

Type of Column

Sepharose (successive elutions)

ngiography

Time Since Last Elution 5 3 3 3 3 3 3

min min min min min min min

24 hr 10 min 10 min

with Time

Breakthrough μΟΙ Hg-195m/mCi Au-195m 0.75 0.32 0.21 0.2 R - S - A u*-C Ν • Auger Electron

R - S - Au*- CN — • ( A u ( C N ) J ~

A

N

Possible Radiolytic Reactions R-S-Hg-CN*e" 0

2

R - S - H g - C N * 0~ F i g u r e 7.

— * R-S-Hg*CN~

5

*e' —*

Some chemical

—> R - S - H g • CN~* 0

6 2

7

r e a c t i o n s o c c u r r i n g on the columns.

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

3.

BETT ET AL.

First-Pass

Angiography

47

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch003

are s p e c u l a t i v e . The nature of the r a d i o l y t i c r e a c t i o n s are even more s p e c u l a t i v e , but one p o s s i b i l i t y i s that the mercury i n the +2 o x i d a t i o n state i s reduced to +1 by r e a c t i o n s such as 5-7 ( F i g u r e 7) and that the r e s u l t i n g gold-sulphur complex i s stronger than the corresponding +2 or +3 complexes mentioned above. Although the column i s only 25% e f f i c i e n t i n e l u t i n g Au-195m i t i s 100% e f f i c i e n t i n e l u t i n g Au-195. Mechanical Aspects of Generator Design. In Table I I the requirements of a generator are l i s t e d i n c l u d i n g the optimal volume of eluant should be about 0.5 ml, and that the generator should a l s o be robust f o r t r a n s p o r t and easy to use. The first requirement means e s s e n t i a l l y no dead volume i n the system. O r i g i n a l designs were based on a modified isotope v i a l with a Luer f i t t i n g i n t o an automatic valve i n t o which a syringe could be i n s e r t e d to draw o f f the a c t i v i t y f o r i n j e c t i o n . This design, shown i n Figure 8, i s now being modified to make i t more robust, although t h i s system has stood up to road, r a i l and a i r t r a n s p o r t without any problems. C l i n i c a l Operation and A p p l i c a t i o n s . A l a r g e number of t e s t s on these generators has now been performed on both animals and humans. The generators are s t e r i l e , non-pyrogenic and very importantly, non toxic. Measurements have shown that a d m i n i s t r a t i o n of the cyanide c o n t a i n i n g eluate has not caused a measurable increase i n plasma cyanide, red c e l l cyanide, or plasma thiocyanate l e v e l s , even when l a r g e volumes are administered (13,14). The l e v e l s remain w i t h i n the normal range f o r non-smoking humans. In p r a c t i c e a c a t h e t e r i s i n s e r t e d i n t o a p a t i e n t ' s forearm and connected to a short length of tube ( v o l . about 0.6 ml) with Luer f i t t i n g s at both ends and terminating i n a 3 way v a l v e , one s i d e of which i s connected to a syringe c o n t a i n i n g 20 ml of s a l i n e . The remaining arm of the valve i s used to i n j e c t the a c t i v i t y so as to j u s t f i l l the tube. This i s followed by the 20 ml of s a l i n e to f o r c e the bolus of a c t i v i t y i n t o the v e i n . A f t e r i n v e s t i g a t i n g various automatic methods t h i s proved s t i l l to be the simplest and s a f e s t method. Measurements of c a r d i a c f u n c t i o n have agreed c l o s e l y with those obtained using Tc—99m (13,14) and Au-195m i s now being used f o r rapid s e q u e n t i a l r a d i o n u c l i d e f i r s t pass angiography to assess e v o l u t i o n a r y changes in cardiac function occurring after pharmocological or p h y s i o l o g i c a l i n t e r v e n t i o n s . The m u l t i p l e data points that may be obtained with Au-195m were p r e v i o u s l y not p o s s i b l e with the f i r s t pass technique. Summary A generator has been produced which i s capable of producing 20 mCi of Au-195m i n about .6 ml. I f care i s taken i n column there i s l e s s than .2 μα Hg-195m/mCi Au-195m i n the eluant. generator has proved robust f o r transport and easy to use, r e l i a b l e , allowing t e s t s i n v o l v i n g over 200 p a t i e n t s .

American Chemical Society Library 1155 16th St. N. w. In Radionuclide Generators; Knapp, F., el al.; D. C. 20038 ACS Symposium Series;Washington, American Chemical Society: Washington, DC, 1984.

10use The and

RADIONUCLIDE GENERATORS

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch003

48

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

3.

BETT ET AL.

First-Pass

Angiography

49

A c k n o w l e dgment s

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch003

We g r a t e f u l l y acknowledge the help of Professor G. H. Coleman i n the e a r l y stages of t h i s work, and a l s o D. L. Stone, P. L. Evans and D. Cooper - students who have a l l contributed g r e a t l y to t h i s work. F i n a l l y our thanks are due t o the V a r i a b l e Energy C y c l o t r o n s t a f f f o r providing proton beams on demand and f o r manufacture of targets and other apparatus. Literature Cited 1. Dymond, D.S.; J a r r e t t , P.H.; B r i t t o n , K.E.; S p u r r e l l , R.A.J. Br. Heart J o u r n a l 1979, 41, 68-78. 2. Jones, T.; Clarke, J.C. B r . J. R a d i o l . 1969, 42,237. 3. Cheng, C.; Treves, S.; Samuel, Α.; Davis, M.A. J . Nucl. Med. 1980, 21,1169-1176. 4. Lebowitz, E.; Richards, P. Semin. N u c l . Med. 1974, 4,257268. 5. Bett, R.; Coleman, G.H.; Cuninghame, J.G.; Sims, H.E; Elliott, A.T.; Stone, D.L. N u c l . Med. Commun. 1981, 2,7579. 6. Bett, R.; Cuninghame, J.G.; Sims, H.E.; Willis, H.H.; Dymond, D.S.; Flatman, W.; Stone, D.L.; Elliott, A.T. I n t . J. Appl. Radiat. I s o t . 1983, 34,959-963. 7. Panek, K.J.; Lindyer, J . ; Van Dei V l u g t , H.C. This volume. 8. Brihaye, C.; Guillaume, M.; L a v i , Ν.; Cogneau, M. J . N u c l . Med. 1982, 23,1114-1120. 9. The Radiochemistry of Mercury NAS-NS-3026. 10. Marchant, W. E n v i r o n . S c i . and Tech. 1971, 8,993-996. 11. Spinks, J.W.T.; Woods, R.J. "An I n t r o d u c t i o n t o R a d i a t i o n Chemistry"; 2nd e d i t i o n ; Wiley-Interscience, New York, 1976. 12. Newton, D.; Sims, H.E. Measurements being c a r r i e d out a t A.E.R.E. Harwell. 13. E l l i o t t , A.T.; Dymond, D.S.; Stone, D.L.; Flatman, W.; B e t t , R.; Cuninghame, J.G.; Sims, H.E.; Willis, H.H. Phys. Med. B i o l . 1983, 28,139-147. 14. Dymond, D.S.; Elliott, A.T.; Flatman, W.; Stone, D.; B e t t , R.; Cuninghame, J.G.; Sims, H.E. J . Amer. C o l l e g e o f C a r d i o l . , in press. RECEIVED

O c t o b e r 17, 1983

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

4 Chemical and Physical Parameters Affecting the Performance of the Os-191/Ir-191m Generator A . B.

PACKARD,

S.

TREVES,

and G .

M.

O'BRIEN

Children's Hospital/Harvard M e d i c a l School, Boston, F. F. KNAPP, JR. and T. A .

MA

02115

BUTLER

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch004

Oak Ridge N a t i o n a l Laboratory, O a k Ridge, TN 37830

The d e v e l o p m e n t o f an Os-191/Ir-191m g e n e r a t o r suitable for radionuclide a n g i o g r a p h y in humans has elicited much interest. This generator employs "[OsO Cl4] on AG MP-1 anion ex­ change resin with a Dowex-2 scavenger column and is eluted w i t h n o r m a l saline a t pH 1. The parent Os species is, however, neither well­ -defined nor homogeneous leading t o less t h a n optimal b r e a k t h r o u g h o f Os-191 (5 x 1 0 - ) and modest Ir-191m yield (10-15%). The effect of a r a n g e o f p a r a m e t e r s on g e n e r a t o r p e r f o r m a n c e has been e v a l u a t e d as has been t h e way in w h i c h t h e a s s e m b l y and l o a d i n g p r o c e s s affects generator performance. In addition, a number o f potential alternative g e n e r a t o r s y s t e m s have been e v a l u a t e d . 2-"

2

3 %

Ultra short-lived radionuclides offer a number o f a d v a n t a g e s o v e r l o n g e r l i v e d i s o t o p e s ( s u c h as Tc-99m) f o r a n g i o c a r d i o g r a p h y . Some o f t h e s e a d v a n t a g e s i n c l u d e t h e a b i l i t y t o o b t a i n s e r i a l images w i t h o u t i n c r e a s e d b a c k g r o u n d , h i g h e r p h o t o n f l u x , and l o w e r p a t i e n t r a d i a t i o n e x p o s u r e ( 1 ) . Such i s o t o p e s a r e c l i n i ­ c a l l y u s e f u l i n t h e e v a l u a t i o n o f a number o f hemodynamic p a r a ­ m e t e r s i n c l u d i n g v e n t r i c u l a r e j e c t i o n f r a c t i o n and i n t r a c a r d i a c s h u n t s as w e l l as e v a l u a t i o n o f c a r d i o v a s c u l a r anatomy. A number o f g e n e r a t o r s y s t e m s have been d e v e l o p e d t o p r o d u c e u l t r a s h o r t - l i v e d isotopes for these applications including Hg-195m/Au-195m, R b - 8 1 / K r - 8 1 m , C d - 1 0 9 / A g - 1 09m, and Os-191/ Ir-191m. The 0s-191/Ir-191m g e n e r a t o r has a number o f advan­ t a g e s o v e r o t h e r s y s t e m s i n c l u d i n g h i g h p h o t o n y i e l d (>90?ό)> l o n g p a r e n t h a l f - l i f e ( T i / 2 = 1 5 . 4 d ) , and t h e a b s e n c e o f b r a n c h i n g pathways. The d i s a d v a n t a g e most o f t e n c i t e d a g a i n s t t h e Os-191/ Ir-191m g e n e r a t o r i s t h e s h o r t h a l f - l i f e o f t h e d a u g h t e r i s o t o p e (4.96 s ) . T h i s i s not a d i s a d v a n t a g e i f a g e n e r a t o r o f s u f f i ­ c i e n t l y h i g h y i e l d c o u l d be p r o d u c e d s i n c e t h e s h o r t h a l f - l i f e l e a d s t o a l o w e r p a t i e n t r a d i a t i o n d o s e and a s h o r t e r r e p l e n i s h 0097-6156/ 84/ 0241 -0051 $06.00/ 0 © 1984 American Chemical Society

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

RADIONUCLIDE GENERATORS

52

ment t i m e f o r t h e g e n e r a t o r between e l u t i o n s . For these reasons, we have d i r e c t e d o u r e f f o r t s t o w a r d s t h e d e v e l o p m e n t o f a g e n e r ­ a t o r f o r Ir-191m t h a t has h i g h e r y i e l d and l o w e r Os-191 b r e a k ­ through than the c u r r e n t d e s i g n . P r o d u c t i o n o f Os-191 Os-191 i s p r o d u c e d by n e u t r o n i r r a d i a t i o n o f i s o t o p i c a l l y e n r i c h e d Os-190 ( i s o t o p i c c o m p o s i t i o n : Os-190, 97.8?ό; Os-188, 0.47%; Os-192, 1 . 0 2 % ) . I r r a d i a t i o n s are c u r r r e n t l y performed at t h e Oak R i d g e N a t i o n a l L a b o r a t o r y i n t h e H i q h F l u x I s o t o p e R e a c t o r ( H F I R ) a t a n e u t r o n f l u x o f 2.5 χ 1 0 ^ n/cm -s. The r o u t e s t o t h e v a r i o u s n u c l i d e s produced d u r i n g i r r a d i a t i o n o f t h e Os-190 t a r g e t and t h e n e u t r o n c r o s s - s e c t i o n v a l u e s (2^) a r e sum­ m a r i z e d b e l o w (Scheme I ) .

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch004

1

2

Scheme I . P r o d u c t i o n scheme f o r Os-191.

Ir-192m 0s-191m σ=9 1 b / \lT,13h o=300by \ IT,1.44m /o=3.9b\ 3",15.4d IT,4.96s/o=624b\ 3~,74d Os-190 -•Os-191 •Ir-^lm ^Ir-191 ^ I r - 1 9 2 — • Pt-192 σ=1100b o=2b 3~,30h ^^o=110b 3",19.1h Os-192—•Os-193 ^Ir-193 •l -194—^Pt-194 r

r

The d i s t r i b u t i o n o f t h e p r o d u c t r a d i o n u c l i d e s was s t u d i e d a s a f u n c t i o n o f i r r a d i a t i o n p e r i o d s o f from 2-14 d a y s ( T a b l e I ) . These d a t a show t h a t i r r a d i a t i o n p e r i o d s o f g r e a t e r t h a n t h r e e o r f o u r d a y s do n o t r e s u l t i n l a r g e i n c r e a s e s i n Os-191 y i e l d b u t do l e a d t o r a p i d i n c r e a s e s i n t h e Os-193, I r - 1 9 2 , and l r - 1 9 4 i m p u r ­ i t i e s . As a r e s u l t , a t h r e e day i r r a d i a t i o n p e r i o d h a s been c h o s e n as a compromise between Os-191 y i e l d and i n c r e a s i n g l e v e l s of i s o t o p i c i m p u r i t i e s . The r a p i d a p p r o a c h o f Os-191 y i e l d t o a maximum v a l u e d u r i n g a 1 4 - d a y i r r a d i a t i o n p e r i o d s u g g e s t s a maximum a t t a i n a b l e s p e c i f i c a c t i v i t y o f a p p r o x i m a t e l y 600 mCi/mg o f e n r i c h e d Os-190 t a r g e t . E x a m i n a t i o n o f Scheme I shows t h a t t h e p r i n c i p a l r o u t e t o Os-191 i s t h r o u g h t h e f o r m a t i o n and s u b s e q u e n t decay o f 0s-191m (T / =13h). The t o t a l y i e l d i s t h u s t h e sum o f t h e O s - 1 9 1 p r o d u c e d by d i r e c t n e u t r o n c a p t u r e by Os-190 and from decay o f 0s-191m. As a r e s u l t , t h e maximum Os-191 y i e l d o c c u r s s e v e r a l h o u r s a f t e r r e m o v a l o f Os-190 t a r g e t from t h e r e a c t o r when t h e 0s-191m h a s d e c a y e d t o O s - 1 9 1 . W i t h i n c r e a s i n g i r r a d i a t i o n 1

2

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

4.

PACKARD ET AL.

Table I

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch004

53

Generator

R a d i o n u c l i d e s Produced p e r M i l l i g r a m o f 97.8% E n r i c h e d Osmium-190

Irradiation t i m e , days 2 3 4 6 10 14

The Os-1911 Ir-191 m

(max) mCi 170 248 308 400 510 552

(45h) (38h) (35h) (30h) (25h) (20h)

194!

3

mCi

mCi

mCi

3.6 5.0 6.6 7.1 8.3 10.7

0.14 0.4 0.9 2.4 5.4 7.5

0.4 1.0 3.4 16.5 35.0

H o u r s o f t a r g e t decay f o l l o w i n g n e u r t r o n i r r a d i a t i o n r e q u i r e d t o a t t a i n t h e maximum ^ ^ 0 s v a l u e due t o a d e l a y e d f o r m a t i o n by 0 s decay ( T / = 1 3 h ) . 1 9 1 m

1

2

p e r i o d s , t h e t i m e r e q u i r e d t o a c h i e v e maximum Os-191 y i e l d a f t e r t a r g e t r e m o v a l d e c r e a s e s s i n c e t h e 0s-191m l e v e l becomes s a t u r a t e d when t h e r a t e o f p r o d u c t i o n e q u a l s t h e r a t e o f d e c a y . The l e v e l o f Os-191 c o n t i n u e s t o i n c r e a s e , h o w e v e r , due t o t h e considerably longer h a l f - l i f e . A second consequence o f i n c r e a s i n g i r r a d i a t i o n p e r i o d s i s i n c r e a s i n g l e v e l s o f Ir-192 (Ti/2=74.2d) produced by n e u t r o n c a p t u r e o f I r - 1 9 1 (Scheme I ) , w h i c h h a s been formed by decay o f t h e s h o r t - l i v e d I r - 1 9 1 m , t h e d a u g h t e r o f Os-191. I t c a n be s e e n from Table I t h a t , f o r i r r a d i a t i o n p e r i o d s o f g r e a t e r than a p p r o x i m a t e l y f o u r d a y s , t h e amount o f I r - 1 9 2 i n c r e a s e s much more r a p i d l y t h a n t h a t o f O s - 1 9 1 . The I r - 1 9 2 c o n c e n t r a t i o n i s a c o n c e r n b e c a u s e t h e p r e s e n c e o f a s i g n i f i c a n t amount o f l o n g l i v e d Ir-192 i n t h e g e n e r a t o r e l u a t e would s i g n i f i c a n t l y i n c r e a s e the r a d i a t i o n dose t o t h e p a t i e n t . The l e v e l s o f I r - 1 9 2 p r e s e n t i n t h e s e t a r g e t s have n o t been f o u n d t o be a s i g n i f i c a n t p r o b l e m , h o w e v e r , b e c a u s e t h e y a r e r e a d i l y removed by w a s h i n g t h e g e n e r a t o r w i t h t h e 4-N HC1 a f t e r l o a d i n g . Radioassay o f the generator e l u a t e a f t e r s u c c e s s i v e w a s h i n g s shows t h e I r - 1 9 2 r a p i d l y d e c r e a s e t o n e g l i g i b l e l e v e l s w h i l e l i t t l e Os-191 i s l o s t . The f e a s i b i l i t y o f p r o d u c i n g Os-191 by i r r a d i a t i o n o f a n a t u r a l ( n o n - i s o t o p i c a l l y e n r i c h e d ) osmium t a r g e t ( 2 6 . 4 % Os-190) has a l s o been i n v e s t i g a t e d . A h i g h p u r i t y osmium m e t a l t a r g e t was i r r a d i a t e d i n t h e H F I R a t t h e same n e u t r o n f l u x a s t h e e n r i c h e d t a r g e t f o r 14 d a y s , p r o c e s s e d i n t h e u s u a l way, and t h e r a d i o n u c l i d e c o m p o s i t i o n d e t e r m i n e d by gamma s p e c t r o m e t r y . The r e s u l t s show, as expected, a wider range o f products are produced than from the isotopically enriched t a r g e t (3). As i n the enriched target, a l a r g e r amount o f Ir-192 i s formed from the i n creasing amounts o f Ir-191 present during prolonged irradiation. In a d d i t i o n , the presence o f a g r e a t e r amount o f Os-192 i n the

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

RADIONUCLIDE GENERATORS

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch004

54

t a r g e t leads to the production of l r - 1 9 4 v i a a s i m i l a r route (Scheme I ) . As i n t h e c a s e o f t h e e n r i c h e d t a r g e t , b o t h I r - 1 9 2 and l r - 1 9 4 may be r e m o v e d by an a p p r o p r i a t e r i n s i n g o f t h e g e n e r a t o r w i t h 4N HC1 p r i o r t o u s e . The o t h e r m a j o r r a d i o c o n t a m i n a n t s p r e s e n t a r e Os-193 and Os-185. The l e v e l o f Os-193 may be r e d u c e d by decay b e c a u s e o f t h e r e l a t i v e l y s h o r t h a l f - l i f e (30.5h). The p r e s e n c e o f s i g n i f i c a n t amounts o f Os-185 i s o f more c o n c e r n , d e s p i t e t h e l o w n a t u r a l abundance o f Os-184 i n t h e target mixture. The l o n g h a l f - l i f e (T

250 ml cone. H P 0 , and 200 ml Ry). 3

4

One

l i t e r of t h i s s o l u t i o n has been used to d i s s o l v e as much as 170 grams of molybdenum metal. This s o l u t i o n i s d i l u t e d with an equal volume of dioxane p r i o r to the s e p a r a t i o n procedure. A second procedure uses 30% H^O^ as a d i s s o l v i n g s o l u t i o n ; f i v e l i t e r s of

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch008

H2O2 have been used to d i s s o l v e about 300 g of the metal. Once a l l the metal has been d i s s o l v e d , the s o l u t i o n i s passed through a c a t i o n exchange column (AG 50W-X8, 100-200 mesh; BioRad L a b o r a t o r i e s ) . A bed volume of as l i t t l e as 40 ml has been used s u c c e s s f u l l y i n t h i s work. The r e s i n removes the c a t i o n s present from the l a r g e q u a n t i t y of molybdate and any other anions that might be present. The column i s now converted to the ammonium form by passing 0.5 M NH^Cl through the column u n t i l the pH of the e f f l u e n t i s the same as the feed s o l u t i o n (^pH 4.5). Next, ap­ proximately f i v e column volumes of 0.5 Μ α-ΗΙΒ (pH 4.5-5.0) are passed through the column. The a-HIB i s now removed from the column v i a an ^ 0 wash. To convert the column back to the hydro­ gen form, about f i v e column volumes of 0.5 M HCl are used. F i n a l ­ l y , strontium i s removed from the column with 6 M HCl. If HNO^-H^PO^ was used i n the d i s s o l u t i o n , the strontium product i s r a d i o c h e m i c a l l y pure and i s evaporated to dryness, d i s s o l v e d i n Η\>0, and then strontium a c t i v i t y i s determined f o r eventual s h i p p i n g .

I f #2®2 was

used, the product contains some

zirconium and i s taken to dryness, d i s s o l v e d i n concentrated HCl, and loaded onto an anion exchange column (AG 1X8, 100-200 mesh; BioRad L a b o r a t o r i e s ) . T h i s i o n exchange step must be performed very soon a f t e r the f i r s t column due to growth of Y-88 from the zirconium contamination. Strontium passes through the anion column; t h i s s o l u t i o n i s evaporated to dryness, d i s s o l v e d i n ^ 0 and prepared f o r shipment. Data A n a l y s i s . A l l samples are analyzed f o r r a d i o a c t i v e n u c l i d e s by a G e ( L i ) - p u l s e height analyzer system c a l i b r a t e d f o r counting 5-ml s o l u t i o n samples. In a l l cases, appropriate d i l u t i o n s are made to reduce the a c t i v i t y l e v e l of the counting sample so that counting system dead-time i s l e s s than 15%. Gamma peak i n t e n ­ s i t i e s are determined using a modified v e r s i o n of the peak f i t t i n g program GAMANAL (11). I n d i v i d u a l n u c l i d e s are determined by i d e n t i f i c a t i o n of t h e i r a s s o c i a t e d gamma r a d i a t i o n s . No h a l f - l i f e measurements are made as part of the i d e n t i f i c a t i o n process. Results L i s t e d i n Table I are the r e s u l t s of nine production runs f o r strontium. Targets ranging i n mass from 64 to 457 grams have been i r r a d i a t e d with production as h i g h as 28 C i at end-of-bombardment

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch008

8.

THOMAS A N D BARNES

Large-Scale

Isolation

of

Sr-82

129

(EOB). Run number 30-1-2 was processed s e v e r a l months a f t e r EOB; t h i s allowed observation of Sr-82 i n the d i s s o l v e d t a r g e t s o l u t i o n . Normally t h i s i s not p o s s i b l e due to the l a r g e number of other n u c l i d e s present s h o r t l y a f t e r i r r a d i a t i o n , s e v e r a l of which have the same gamma ray energy as Sr-82. Measurement of Sr-82 i n the t a r g e t s o l u t i o n of run 30-1-2 allowed an e s t i m a t i o n of the strontium o v e r a l l chemical y i e l d . This was determined to be _>90%. The o v e r a l l y i e l d on some of the l a t e r runs was roughly estimated to be 50-75%. In these s t u d i e s some strontium y i e l d was s a c r i f i c e d to i n s u r e a pure f i n a l product and to shorten the time i n v o l v e d i n preparing the sample f o r s h i p p i n g . The r a t i o ôf Sr-82 to Sr-85 at EOB i s a l s o shown i n Table I. The Sr-83 to Sr-82 r a t i o has been determined f o r the l a s t three runs. This r a t i o was determined to be 7.2, 6.5, and 3.0 f o r runs 33-1-14, -18, and -21, r e s p e c t i v e l y . The times required f o r the various procedure steps are given i n Table I I . The d i s s o l u t i o n takes as long as three hours no matter which technique i s used. S o l u t i o n and column p r e p a r a t i o n time i s roughly three hours and clean-up and waste d i s p o s a l take about four hours.

Table I.

Run

No.

30-1-2 33-1-1 33-1-3 33-1-4 33-1-9 33-1-13 33-1-14 33-1-18 33-1-21

Hours i n Beam

uA-hr 2.27 1.92 2.24 1.16 3.16 1.60 5.18 4.92 4.08

Production of Sr-82

χ 10^ χ 10^ χ 10^ χ 10^ χ 10^ χ 10^ χ 10 χ 10 χ 10 4

4

5

654 47 569 ^350 677 403 142 125 695

Target Mass 457 166 334 166 64 450 64 167 289

Total Ci Sr-82 at EOB

Ratio at EOB 82/85

24.0 1.1 28.0 9.6 ^12.0

* 1.7 5.1 20.0

1.16 1.28 λ,Ι.ΟΟ

1.12 1.13 1.06 1.38 1.43 1.05

*Not a l l of t a r g e t d i s s o l v e d . Discussion The 0.5 M NH^Cl wash of the i o n exchange column i s a good decon­ tamination step f o r rubidium r a d i o i s o t o p e s and a l s o removes some cobalt and vanadium. Often, the ammonium c h l o r i d e and the a-HIB s o l u t i o n s appear blue-green which probably r e s u l t s from massive amounts of copper from the t a r g e t packaging. Both of these column

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

130

RADIONUCLIDE GENERATORS

Table II·

Time Requirements f o r the New

Step

Time Required

Dissolution Cation Column Evaporation Anion Column Evaporation

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch008

Strontium

Process

(hours)

^3 50 mCi/ml D i l u t e HCl

Radionuclidic Purity*: Sr-85 Sr-83 Rb-83 A l l Other

15 mCi/mCi Sr-82

CM

δ

α>

ώ

CM

ΙΟ CM CM

9,




6

ΙΟ

*

CO

*

1.4

•3

CO

i

I

ΙΟ

σ> ο

CM

CM


ο

CM

h

9

Ν

CO CO

CD CO

I Ο χ

CM

s

*

s S

i

CO

ΙΟ

σ> ο

ΙΟ ΙΟ ΙΟ

κ

CM

CM

* *

e

CM

* * *

CM

CO

I

δ I

υ

ο "S

u ΙΟ CL

Ill "~

•β

σ>

6

i

< χ

CM

οί

CO

Ν

Ο


25,000 21,000

*R. D. N e i r i n c k x , J . F. Kronauge, and M. D. Loberg, I n t . J . Appl. Radiât. Isotopes, 3k: 721-25 (1983).

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

GENNARO ET AL.

Pharmaceutical

Quality

Rb-82

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch009

9.

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

139

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch009

140

RADIONUCLIDE GENERATORS

r a t e . Furthermore, other considerations i n the design of an i n ­ f u s i o n system should include the f o l l o w i n g : 1. The pharmaceutical requirement to maintain eluate s t e ­ r i l i t y and a p y r o g e n i c i t y , 2. Minimum dead volume o f eluate tubing to reduce decay during a d m i n i s t r a t i o n , 3. P h y s i c a l strength to withstand frequent use over long periods, 4. Control o f volume and r a t e o f d e l i v e r y , 5. Real-time d i s p l a y of e l u t e d a c t i v i t y and the means o f terminating the i n f u s i o n at a pre-set p a t i e n t administered dose, 6. Choice o f continuous or bolus i n f u s i o n modes, and 7. V a l v i n g to d i v e r t low s p e c i f i c concentration eluate to "waste". Syringe d e l i v e r y systems containing many of these f e a ­ tures have been developed at the U n i v e r s i t y of C a l i f o r n i a (8-11), and t h i s system i s described i n d e t a i l by Yano, Budinger, Cahoon and Huesman i n t h e i r chapter i n t h i s volume. We have developed and tested a Rb-82 i n f u s i o n system that incorporates a l l o f these features (Figure 2). The system i s a mobile, s e l f - c o n t a i n e d pump, generator, and dosimeter (Figure 3 ) . The electromechanical syringe pump can be set to d e l i v e r s a l i n e at any flow r a t e from 10 to 100 ml/minute. S a l i n e i s t r a n s f e r r e d through s t e r i l e tubing to a 150 ml s t e r i l e , disposable p l a s t i c syringe. Check valves at the syringe output a u t o m a t i c a l l y d i r e c t the eluent i n e i t h e r f i l l i n g or i n f u s i o n modes. The generator i s connected to the system by s t e r i l e , PVC l u e r - l o c k tubing and i s contained w i t h i n a lead s h i e l d one and one h a l f inches t h i c k . The eluate a c t i v i t y i s c a r r i e d through PVC tubing past a r a d i a t i o n de­ t e c t o r and through a two-way microprocessor c o n t r o l l e d v a l v e , which d i r e c t s the eluate to e i t h e r the subject or to a waste c o l ­ l e c t i o n b o t t l e , both o f which terminate i n a 0.22 μ s t e r i l i z i n g filter. The p o s i t i o n of t h i s valve i s determined by the e l u t i o n mode s e l e c t e d at the c o n t r o l module. The i n f u s i o n system may be set to e l u t e the generator a t any preset flow r a t e i n any of the f o l l o w i n g modes: 1. Volume p r i o r i t y , i n which the i n f u s i o n w i l l stop when the p a t i e n t has r e c e i v e d a preset volume ( m l ) . 2. Dose p r i o r i t y , i n which the i n f u s i o n w i l l stop when the p a t i e n t has r e c e i v e d a preset dose (mCi). 3. Bolus p r i o r i t y , i n which the eluate i s d i r e c t e d i n i ­ t i a l l y to the waste c o l l e c t i o n b o t t l e u n t i l the onset of the bolus (adjustable onset l e v e l , mCi/sec) d i v e r t s the eluate stream to the p a t i e n t l i n e u n t i l the preset dose i s accumulated. Experimental Generator P r e p a r a t i o n . Strontium-82 i s obtained from Los Alamos National Laboratory (LASL). The isotope i s produced by a high energy s p a l l a t i o n r e a c t i o n on molybdenum and the p u r i f i e d mixture contains other strontium isotopes, notably Sr-83/Rb-83 and Sr-85.

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

GENNARO ETAL.

Pharmaceutical

Quality

Rb-82

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch009

9.

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

141

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch009

RADIONUCLIDE GENERATORS

F i g u r e 3. M o b i l e , s e l f - c o n t a i n e d i n f u s i o n s y s t e m f o r Rb-82 g e n e r a t o r .

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch009

9.

GENNARO ET AL.

Pharmaceutical

Quality

143

Rb-82

R a d i o n u c l i d i c analyses are performed with e i t h e r a l i t h i u m - d r i f t e d germanium or i n t r i n s i c germanium d e t e c t o r . The assay f o r Sr-82 i s based upon i t s 777 keV photon of 13.6% abundance. Strontium-85, which i s o f t e n present i n amounts comparable to that o f Sr-82, i s assayed by i t s 514 keV photopeak, which must be resolved from prominent 511 keV a n n i h i l a t i o n r a d i a t i o n by a curve s t r i p p i n g procedure (L2). Up to 150 mCi of Sr-82 ( c o n t a i n i n g up to 300 mCi of Sr-85) i s t r a n s f e r r e d to a column containing hydrous t i n oxide. The column i s washed with 0.9% sodium c h l o r i d e to remove Rb-83 radiocontami n a n t s . This column i s f i t t e d with l u e r - l o c k connectors to f a c i l i t a t e i t s use with s t e r i l e PVC tubing. The generator i s eluted with 0.9% sodium c h l o r i d e . The eluent i s d e l i v e r e d by the syringe pump of the i n f u s i o n system. Eluates are c o l l e c t e d i n 50 ml stoppered v i a l s f o r nuclear and chemical analyses. Rb-82 may be conv e n i e n t l y measured i n an i o n chamber (dose c a l i b r a t o r ) . We have confirmed that the potentiometer s e t t i n g recommended by the i n strument manufacturer (Capintec, Montvale, Nj) i s accurate. A sample of f r e s h l y eluted Rb-82 was measured by both a dose c a l i brator and, a f t e r s u i t a b l e decay, a c a l i b r a t e d G e ( L i ) spectrometer system. Data f o r both instruments l a y along a s i n g l e exponential decay of 76 sec h a l f - l i f e . Our e v a l u a t i o n of the Sr-82/Rb-82 generator performance i s based p r i m a r i l y on measurement of y i e l d , breakthrough, and e l u t i o n p r o f i l e . Y i e l d . The Rb-82 content of 50 ml of e l u a t e , decay c o r r e c t e d to end of e l u t i o n , c o l l e c t e d at 50 ml/min i s measured i n a Capintec CRC-17 dose c a l i b r a t o r using the potentiometer s e t t i n g recommended by the manufacturer f o r Rb-82. While t h i s datum i s not as s i g n i f i c a n t as the dynamic y i e l d information obtained from measurement of e l u t i o n p r o f i l e s , i t i s valuable i n p r e l i m i n a r y development work and i n monitoring the performance of a given u n i t through an extended use p e r i o d . Breakthrough. Eluate r a d i o n u c l i d i c p u r i t y i s determined by Nal s c i n t i l l a t i o n spectrometry on 50 ml of e l u a t e . Samples must be held at l e a s t one hour before measurement to allow f u l l decay of Rb-82. To improve s e n s i t i v i t y o f measurement, the most prominent 511+514 keV peak i s counted. Computations are based upon comparison with an a l i q u o t of Sr-82+Sr-85 s o l u t i o n used to prepare the generator.. Data are expressed i n u n i t s of y C i Sr-82/ml of eluate/ mCi Rb-82 at end of e l u t i o n . E l u t i o n P r o f i l e . E l u t i o n p r o f i l e s are determined with the i n - l i n e r a d i a t i o n detector. For c a l i b r a t i o n of the i n - l i n e detector, equations developed f o r q u a n t i t a t i v e radiochromatography may be adapted. For a s i n g l e d e t e c t o r , isotope, and geometry, which i s i n e f f e c t c o n t r o l l e d by the tubing used to c a r r y the eluate past the detector, a simple expression can be w r i t t e n (Eq. 2): A = C-F/K

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

(2)

RADIONUCLIDE GENERATORS

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch009

144

where A = the i n t e g r a t e d a c t i v i t y i n mCi; C = counts; F = flow r a t e of eluate i n ml/min; and Κ = constant of p r o p o r t i o n a l i t y . The flow r a t e term i s kept independent of the p r o p o r t i o n a l i t y constant to allow f o r separate adjustment of the flow r a t e without the need to r e a d j u s t the c a l i b r a t i o n f a c t o r f o r the d e t e c t o r . Thus, the s c a l e r s on the dosimeter module may be set to d i s p l a y i n mCi of Rb-82, since the c i r c u i t incorporates an adjustable pulse d i v i d e r corresponding to the p r o p o r t i o n a l i t y constant. In a d d i t i o n to d i s p l a y i n g the a c t i v i t y of Rb-82 passing the detector at any i n s t a n t , the second s c a l e r provides a summation of t o t a l a c t i v i t y e l u t e d . The flow r a t e constant, F, i s set equal to the flow r a t e c o n t r o l of the i n f u s i o n pump. The c a l i b r a t i o n of the i n - l i n e detector i s accomplished by comparing the e n d - o f - e l u t i o n c o l l e c t e d dose (as measured i n a dose c a l i b r a t o r ) to the d i f f e r e n t i a l e l u t i o n p r o f i l e (as measured by the i n - l i n e d e t e c t o r ) . With data c o l l e c t i o n at 1 sec i n t e r v a l s , a 50 ml e l u t i o n at 50 ml/min w i l l produce 60 data p o i n t s ( t O , each of which must be c o r r e c t e d to e n d - o f - e l u t i o n . The c a l i b r a t i o n f a c t o r f o r the i n - l i n e detector may be c a l c u l a t e d from a s i n g l e e l u t i o n (Eq. 3) where EOE i s the end of e l u t i o n . ΣΝ. e ^ K

-

C

>

F

/

A

"

' F (ml/min)

Rb-82 (mCi, EOE)

( 3 )

Results and D i s c u s s i o n The Rb-82 generators thus prepared were evaluated by r e p e t i t i v e , high volume e l u t i o n s using the i n f u s i o n system described e a r l i e r . Eluent was e x c l u s i v e l y s t e r i l e , 0.9% sodium c h l o r i d e s o l u t i o n with c o l l e c t i o n s made i n t o s t e r i l e , vented serum v i a l s .

Y i e l d . The Rb-82 content of 50 ml eluates c o l l e c t e d at 50 ml/min i s 71.7±6.5% of the Sr-82 potency of the generator. Frequent e l u t i o n s over extended periods w i l l s l i g h t l y improve t h i s value. 4 f t e r three weeks e l u t i o n with 2 l i t e r s o f 0.9% sodium c h l o r i d e , the c o l l e c t e d end of e l u t i o n y i e l d w i l l be 5-10% greater than i n i t i a l yields. 1

E l u t i o n P r o f i l e . The d i f f e r e n t i a l e l u t i o n p r o f i l e s at three d i f f e r e n t flow r a t e s are shown i n Figure 4. As expected, the Rb-82 y i e l d improves at f a s t e r flow r a t e s with l e s s a c t i v i t y being l o s t to decay. I n t e g r a l outputs are shown i n Figures 5 and 6. These values represent, r e s p e c t i v e l y , the administered dose and the c o l l e c t e d dose. The former data, which represent the i n t e ­ grated dosimeter readings of the o n - l i n e d e t e c t o r , must be con­ sidered i n e s t a b l i s h i n g the d u r a t i o n of i n f u s i o n c o n s i s t e n t with

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch009

9.

G E N N A R O ET AL.

Pharmaceutical

Quality

Rb-82

Figure h. Elution p r o f i l e of Rb-82 as a function of time for three selected flow rates.

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

145

RADIONUCLIDE

GENERATORS

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146

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

9.

GENNARO ET AL.

Pharmaceutical

Quality

Rb-82

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch009

Δ 75 ml/min

(Minutes) F i g u r e 6. S t e a d y - s t a t e a d m i n i s t e r e d a c t i v i t y f r o m a Rb-82 g e n e r a t o r a s a f u n c t i o n o f t i m e f o r t h r e e s e l e c t e d flowrates .

American Chemical Society Library 1155 16th St. N. W. In Radionuclide Generators; Knapp, F., el al.; Washington. D. C. 20038 ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

147

148

RADIONUCLIDE GENERATORS

10-3

CM

00 I

10~

4

η CO Ο Ε

• ΙΟ"

5

CM CO

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch009

CO Δ Ο

ϋ

Δ

Ο

Δ η 0

*

0

Δ

Α

Δ

0

§

η

10-6-

10-7

1

2

3

Eluent Volume (L)

F i g u r e 7· S t r o n t i u m - 8 2 b r e a k t h r o u g h f o r e l u t i o n s a t 50 mL/min.

_l 30

I 50

I 70

1 85

collected

L_ 100

Elution Speed (ml/min)

F i g u r e 8. rate.

S t r o n t i u m - 8 2 b r e a k t h r o u g h as a f u n c t i o n o f f l o w

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

9.

GENNAROETAL.

Pharmaceutical

Quality

Rb-82

149

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch009

the p a t i e n t absorbed dose. The l a t t e r data, which are decay c o r ­ r e c t e d , i n d i c a t e the i n - v i v o r a d i o c o n c e n t r a t i o n during the i n ­ f u s i o n . At a nominal flow r a t e of 50 ml/min, approximately 8 0 % of the f u l l generator potency w i l l be a v a i l a b l e f o r d i a g n o s t i c imaging. Chemical P u r i t y . Selected eluates from a 4 l i t e r e l u t i o n program were subjected to analyses f o r chemical and b i o l o g i c a l p u r i t y . At the end o f four weeks o f continued use, during which 4 l i t e r s of eluate were c o l l e c t e d , samples were s t e r i l e and non-pyrogenic. I s o t o n i c i t y was confirmed (NaCl = 8.94±.03 mg/ml) and n e u t r a l i t y maintained (pH = 6.27±0.16). No t i n was detected i n generator eluates by d i f f e r e n t i a l pulse polarography above a d e t e c t i o n l i m i t o f 0.1 yg/ml. The r a d i o n u c l i d i c i d e n t i t y o f Rb-82 i s e a s i l y confirmed by v e r i f i c a t i o n of i t s 76 sec h a l f - l i f e or through gamma spectrometry. Breakthrough. Strontium-82 contamination of e l u a t e s from three generators i s shown i n F i g u r e 7 f o r t o t a l e l u t i o n volumes o f 4 liters. Breakthrough i s l e s s than 1 χ 10 y C i Sr-82/ml/mCi Rb-82 throughout the t e s t p e r i o d . Other generators have been e l u t e d to t o t a l volumes o f 20 l i t e r s , with no i n c r e a s e i n break­ through above 1 χ 10 y C i Sr-82/ml/mCi Rb-82. Furthermore, low breakthrough l e v e l s are maintained up to flow r a t e s o f 100 ml/min (Figure 8 ) . Summary The rubidium-82 eluate from t h i s generator system i s pharmaceutic a l l y s u i t a b l e f o r d i r e c t venous i n f u s i o n . Imaging may be based on p o s i t r o n emission tomography (1^) . A l t e r n a t i v e l y , images o f d i a g n o s t i c q u a l i t y should be a n t i c i p a t e d from s i n g l e photon de­ t e c t i o n systems, provided that the instrumentation i s compatable with these high energy photons. The f e a s i b i l i t y o f modifying con­ v e n t i o n a l instruments f o r Rb-82 has been demonstrated by Ryan, e t . a l . ( 1 4 ) and Cochavi, £t.al. (15). Thus Rb-82, as produced and administered by t h i s system, may have p o t e n t i a l c l i n i c a l u t i l i t y f o r myocardial p e r f u s i o n (16) , e v a l u a t i o n o f b r a i n tumors (1J3), and kidney imaging ( 15) . Literature Cited 1. 2. 3. 4.

K e a r f o t t , K.J. J. Nucl. Med. 1 9 8 2 , 2 3 , 1128-1132. Yano, Y.; Roth, E. P. I n t . J. Appl. Radiat. Isotopes 1979, 3 0 , 382-385. K u l p r a t h i p a n j a , S.; Hnatowich, D.J.; Beh, R. I n t . J. A p p l i e d Radiat. Isotopes 1979, 3 0 , 447-449. Horlock, P.L.; C l a r k , J.C.; Goodier, I.W.; Barnes, J.W.; Bentley, G.E.; Grant, P.M.; O'Brien, H.A. J . Radioanal. Chem. 1 9 8 1 , 6 4 , 257-265.

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

150 5.

6. 7. 8. 9. 10.

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch009

11. 12.

13.

14.

15.

16.

RADIONUCLIDE GENERATORS

N e i r i n c k x , R.D.; Kronauge, J.F.; Gennaro, G.P.; Loberg, M.D.; Los Alamos Medical Radioisotope Group, J. Nucl. Med. 1982, 23, 245-249. Brihaye, Cl.; Guillaume, M.; Cogneau, M. Radiochem. Radioa n a l . L e t t e r s 1981, 48, 157-164. Guillaume, M.; Brihaye, Cl. J. Biophys. Med. Nucl. 1982, 6, 137-142. Yano, Y.; Anger, H.O. J . Nucl. Med. 1968, 9, 412-415. Budinger, T.F.; Yano, Y.; Hoop, B. J. Nucl. Med. 1975, 16, 429-431. Yano, Y.; Budinger, T.F.; Chiang, G.; O'Brien, H.A.; Grant, P.M. J . Nucl. Med. 1979, 20, 961-966. Yano, Y.; Cahoon, J.L.; Budinger, T.F. J . Nucl. Med. 1981, 22, 1006-1010. Waters, S.L.; B u t l e r , K.R.: C l a r k , J.C.; Horlock, P.L.; Kensett, M.J.; Goodier, I.W.; Makepeace, J . ; Smith, D.; Woods, M.J.; Barnes, J.W.; Bentley, G.Ε.; Grant, P.M.; O'Brien, H.A. I n t . J . Appl. Radiat. Isotopes 1983, in p r e s s . Yen, C.-K.; Yano, Y.; Budinger, T.F.; F r i e d l a n d , R.P.; Derenzo, S.E.; Huesman, R.H.; O'Brien, H.A. J . Nucl. Med. 1982, 23, 532-537. Chua, K.G.; Ryan, J.W.; A l - S a d i r , J . ; Resnekov, L.; Harper, P.V. IX World Congress of Cardiology, Moscow, June 20-26, 1982. N e i r i n c k x , R.D.; Cochavi, S.; Gennaro, GP.; Loberg, M.D.; Kronauge, J.F.; Goldsmith, S.L.; O'Brien, H.A. III World Congress of Nuclear Medicine and B i o l o g y , P a r i s , Aug. 29 Sept. 2, 1982. Budinger, T.F.; Yano, Y.; Derenzo, S.E.; Huesman, R.H.; Cahoon, J.L.; Moyer, B.R.; Greenberg, W.L.; O'Brien, H.A. J . Nucl. Med. 1979, 20, 603.

RECEIVED

August 19, 1983

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

10 Evaluation of Adsorbents for the Ta-178 Generator R. D . N E I R I N C K X — D e p a r t m e n t o f Radiology, H a r v a r d M e d i c a l S c h o o l , Boston, MA 02115 J.

TRUMPER—Soreq

A.

LEBLANC

Nuclear Research Center, Yavne, Israel

and P. C . J O H N S O N — N a t i o n a l Air and Space A d m i n i s t r a t i o n , Life Sciences

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch010

D i v i s i o n , H o u s t o n , TX 77058

The c u r r e n t l y used Ta-178 generator is based on a r a d i a t i o n s e n s i t i v e adsorbent and can be eluted about 5 0 times before W-178 breakthrough becomes unacceptable. We evaluated a s e r i e s of i n o r g a n i c and organic adsorbents as support f o r t h i s generator. Hydrated inorganic m a t e r i a l s adsorb tantalum very s t r o n g l y from most aqueous s o l u t i o n s and none was found u s e f u l f o r the W-178/Ta-178 generator. Tantalum comp l e x i n g agents are not able to desorb tantalum without d i s s o l v i n g the adsorbents to an a p p r e c i able extent. C h e l a t i n g r e s i n s with a high affinity f o r W were i n v e s t i g a t e d because they could reduce the W-178 breakthrough. They a l s o adsorb tantalum too s t r o n g l y to be s u i t a b l e as substrates f o r the Ta-178 generator.The Bio-Rad AG1x8 system was found to be s u p e r i o r to the other tested systems. The e f f e c t s of a u t o c l a v i n g , complexant a d d i t i v e s and prolonged e l u t i o n on the Ta-178 y i e l d were measured and the chemical breakdown products quantitated. The usefulness of generator-derived s h o r t - l i v e d r a d i o n u c l i d e s i s w e l l e s t a b l i s h e d . The p r i n c i p a l advantages are the opportunity to perform r a p i d repeat s t u d i e s a f t e r various i n t e r v e n t i o n s and the use of high l e v e l s of a c t i v i t y without s u b j e c t i n g the p a t i e n t to an unacceptable r a d i a t i o n dose. S p e c i a l detectors are necessary f o r the d e t e c t i o n of these high a c t i v i t i e s of r a d i o n u c l i d e s s i n c e the standard Anger-camera i s not able to handle such high count r a t e s . One i s p r a c t i c a l l y l i m i t e d to m u l t i - c r y s t a l cameras or gas cameras l i k e the multi-wire p r o p o r t i o n a l (MWPC) or the gas s c i n t i l l a t i o n counters. This implies that the electromagnetic r a d i a t i o n of the r a d i o n u c l i d e should p r e f e r a b l y be of low energy, as these are most s u i t a b l e

0097-6156/ 84/ 0241 -0151 $06.00/ 0 © 1984 A m e r i c a n C h e m i c a l S o c i e t y

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

152

RADIONUCLIDE GENERATORS

f o r e f f i c i e n t d e t e c t i o n with gas d e t e c t o r s . Such low-energy electromagnetic r a d i a t i o n can be found i n the c h a r a c t e r i s t i c x-rays of heavy elements. Tantalum-178 (Ta-178) i s a s h o r t - l i v e d r a d i o n u c l i d e ( T ^ -

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch010

2

9.3 min) that decays with emission of c h a r a c t e r i s t i c hafnium x-rays which are e f f i c i e n t l y detected by the MWPC. The usefulness of Ta-178 l i e s mainly i n the low p a t i e n t r a d i a t i o n - d o s e per mCi i n j e c t e d . The high a c t i v i t i e s that can be i n j e c t e d generate the high photon f l u x e s that allow an accurate e v a l u a t i o n of f a s t p h y s i o l o g i c processes. The p r i n c i p a l use of Ta-178 has been i n the assessment of the l e f t v e n t r i c u l a r e j e c t i o n f r a c t i o n (1_>2) · A generator f o r the production of Ta-178 has been described e a r l i e r (1). I t i s based on an organic anion-exchange r e s i n which i s s e n s i t i v e to r a d i o l y s i s . The d i s t r i b u t i o n c o e f f i c i e n t f o r tungsten (W) under the s e p a r a t i o n c o n d i t i o n s i s low (_2), which r e s u l t s i n increased W-178 breakthrough a f t e r approximately 50 c o l l e c t i o n s . Furthermore, the e l u a t e has not p r e v i o u s l y been evaluated f o r organic r e s i n breakdown products. T h i s paper summarizes the r e s u l t s of a thorough e v a l u a t i o n of the e x i s t i n g Ta-178 generator and an e v a l u a t i o n of a l t e r n a t i v e adsorbents, most of them i n o r g a n i c , as generator support media. Experimental Radionuclide P r o p e r t i e s of Ta-178. Tantalum-178 i s formed from the decay of i t s parent W-178 ( T j y ) h a l f - l i f e of 9.3 minutes y i e l d i n g s t a b l e Hf-178. The decay of the parent i s o t o p e (W-178) occurs e n t i r e l y by e l e c t r o n capture to the 9.3 minute Ta-178 s t a t e , without feeding the h i g h s p i n Ta-178 isomer ( h a l f - l i f e 2.4 h r s ) . In Ta-178 decay, 99.2% of the d i s i n t e g r a t i o n s proceed by e l e c t r o n capture and 0.8% by p o s i t r o n emission. E l e c t r o n capture r e s u l t s i n a 61.2% branch to the ground s t a t e of Hf-178 and 33.7% to the f i r s t e x c i t e d s t a t e at 93.1 keV. The balance, 4.3%, feeds hafnium l e v e l s between 1175 and 1772 keV. The most prominent f e a t u r e s of the energy spectrum of t h i s r a d i o n u c l i d e are the hafnium c h a r a c t e r i s t i c x-rays with energies between 54.6 and 65.0 keV. =

2

1

,

7

d

9 a

n

d

h

a

s

a

2

M a t e r i a l s . A number of i n o r g a n i c and organic adsorbents were evaluated. A l l the i n o r g a n i c m a t e r i a l s are hydrates and were evaluated i n combination with i n j e c t a b l e aqueous s o l u t i o n s . Complexing agents were added to some eluents i n order to reduce tantalum a d s o r p t i o n . C h e l a t i n g r e s i n s , such as the p y r o g a l l o l formaldehyde copolymer, were tested f o r t h e i r a d s o r p t i o n of tungsten. The adsorption of tantalum onto non-hydrated adsorbents such as the organic adsorbent Bio-Rad AGlx8 and s i l y l a t e d s i l i c a were evaluated.

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch010

10.

NEIRINCKX ET AL.

Adsorbents

for the Ta-178

153

Generator

The f o l l o w i n g chromatographic i n o r g a n i c adsorbents were donated by A p p l i e d Research SPRL (Belgium): hydrous t i t a n i u m oxide, t i t a n i u m oxide-hydrogen peroxide hydrate, hydrous zirconium oxide, hydrous f e r r i c oxide, hydrous s t a n n i c oxide, polyantimonic a c i d , s i l i c i c a c i d , hydrous chromium oxide, hydrous manganese d i o x i d e , zirconium phosphate, t i n phosphate, Phomix (20% ammonium phosphotungstate i n zirconium phosphate), S i p h o z i r (zirconium p h o s p h a t e - s i l i c a t e ) , chromium phosphate, t i t a n i u m phosphate, molybdenyl f e r r o c y a n i d e , zirconium f e r r o c y a n i d e , f e r r i c f e r r o c y a n i d e and K-Co f e r r o c y a n i d e . Alumina was obtained from Woelm (Eschwege, Germany). Tungsten c a r b i d e , non-chromâtοgraphic, was obtained from P f a l t z and Bauer (Stamford, Conn.). Tungsten d i s u l f i d e was obtained from Alfa-Ventron (Danvers, Mass.). Bio-Rad AGlx4A was obtained from Bio-Rad (Richmond, Ca.). Some i n o r g a n i c m a t e r i a l s were synthesized i n our l a b o r a t o r y . T h i s group included t u n g s t i c a c i d , C a F and S r F ^ c o a t e d A l ^ , anhydrous Sn0 , T i 0 , S i 0 , 2

2

2

2

CrOg, Mn0 , t i n phosphate, zirconium phosphate, t i t a n t i u m 2

phosphate, molybdenyl f e r r o c y a n i d e , zirconium f e r r o c y a n i d e and f e r r i c ferrocyanide. with a B 0 2

of

3

Tungstic a c i d was produced by h e a t i n g

WO^

f l u x to 1,200°C, c o o l i n g the melt to 800°C at a r a t e

2°C/hour and then to room temperature.

The C a F - or

S r F - c o a t e d A1 0~

2

were prepared by treatment of an A1 0~ 2 + 2 + adsorbent, saturated with Ca or Sr with a NaF s o l u t i o n . C o n t r o l l e d pore g l a s s beads (237 A mean diameter) were obtained from E l e c t r o n u c l e o n i c s , Inc. ( F a i r f i e l d , NJ). S i l a n e Z-6020 was obtained from Dow-Corning. Two kinds of chelate r e s i n were synthesized and evaluated: A pyrogallol-formaldehyde copolymer 03,4) and a copolymer of alphabenzoin oxime with formaldehyde. Bio-Rad AGlx8 200-400 mesh was used as adsorbent to evaluate the published generator method ( 1 ) . S i l y l a t e d s i l i c a g e l was prepared according to the procedure of Leyden, et a l ( 5 ) . F i n e g r a i n s of c o n t r o l l e d - p o r e g l a s s beads (CPG) were heated f o r three hours with 100 ml of a 10% s o l u t i o n of Z-6020 s i l a n e i n toluene. The f i l t e r e d and toluene-washed product was d r i e d overnight at 80 C and used as a tungsten-adsorbent. ?

9

Determination of P a r t i t i o n C o e f f i c i e n t s (Kp).

9

The Kp values of W

and Ta between the adsorbents and v a r i o u s mobile phases of i n t e r e s t were measured by batch e q u i l i b r a t i o n . The f i r s t adsorbent was p r e - e q u i l i b r a t e d three times with the l i q u i d phase, and the supernate decanted. The batch e q u i l i b r a t i o n was performed using 100 mg of adsorbent and 5 grams of mobile phase, to which a W-178-Ta-178 mixture was added. The two phases were then shaken f o r 10 minutes by means of a Hematec A l i q u o t mixer.

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

154

RADIONUCLIDE GENERATORS

A f t e r c e n t r i f ligation, samples from each phase were analyzed f o r W-178 and Ta-178 u s i n g a Ge ( L i ) detector coupled to a Nuclear Data ND60 Y-spectrophotometer. Tantalum-178 was quantitated using i t s 93 keV gamma-ray. A f t e r c o r r e c t i o n f o r p h y s i c a l decay, the Kp values are c a l c u l a t e d as the r a t i o of the c o n c e n t r a t i o n s of the element i n the s t a t i c and the mobile phase ( 2 ) . Since the concentrations are p r o p o r t i o n a l to the r a d i o a c t i v i t y l e v e l

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch010

=

a c t i v i t y of r a d i o n u c l i d e / g adsorbent a c t i v i t y of r a d i o n u c l i d e / g mobile phase

where the adsorbent i s always weighed as an a i r - d r i e d powder. Tungsten-178 was quantitated a f t e r both f r a c t i o n s were allowed to decay f o r 90 minutes and by counting the e q u i l i b r i u m a c t i v i t y of Ta-178 a s s o c i a t e d with the W-178. The Kp-values were c a l c u l a t e d as f o r tantalum. Adsorption S t u d i e s .

The i n o r g a n i c adsorbents l i s t e d above were -3 evaluated with the f o l l o w i n g non-complexing e l u e n t s : 10 Ν H C l , 0.1N

NaOH, 0.25% Na HP0 .7H 0, 0.9% NaCl and 0.1% NaHS0 . The 2

4

2

3

adsorption of W and Ta onto organic adsorbents was a l s o e v a l ­ uated. The W and Ta adsorption onto the pyrogallol-formaldehyde r e s i n was evaluated with aqueous mobile phases as a f u n c t i o n of pH. The Kp of W and Ta between s i l i c a or s i l y l a t e d s i l i c a and mobile phases c o n t a i n i n g d i l u t e HCl or 1% NaF were determined. An attempt to improve the adsorption of W onto Dowex 1x8 was made by converting the loaded W-178 a c t i v i t y to phosphotungstate, e i t h e r by r e c r y s t a l l i z i n g the phosphotungstate and u s i n g i t s HCl s o l u t i o n s or by forming i t i n s i t u by means of 3 ^ direct H

e v a l u a t i o n of t h i s s o l u t i o n .

P 0

a

n

d

The Kp values f o r W and Ta between

Bio-Rad AGlx4 and HCl s o l u t i o n s of d i f f e r i n g n o r m a l i t y were a l s o -2 -1 determined. The e f f e c t of the a d d i t i o n of 10 M or 10 M ^PO^ to the 0.1 Ν HCl mobile phases was measured. The Kp values f o r W and Ta between e i t h e r HCl or NaF s o l u t i o n s and the c h e l a t i n g r e s i n Chelex 100 were determined as a f u n c t i o n of the pH of the mobile phase. The adsorption of W and Ta onto i n o r g a n i c adsorbents from mobile phases c o n t a i n i n g f l u o r i d e was a l s o s t u d i e d . The Kp values o f W and Ta between f l u o r i d e c o n t a i n i n g aqueous phases and Mn0 , Ti-phosphate, S i 0 s i l y l a t e d S i 0 and S r F were determined 2

2 >

2

2

as a f u n c t i o n of the pH of the mobile phase. the

r a t e of adsorption of W and Ta onto Z r O

?

A study was made of from a 0.1%

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

10.

NEIRINCKX ETAL.

Na-oxalate

solution

Adsorbents

for

the Ta-178

155

Generator

and onto MnO^ from 1% NaF s o l u t i o n s .

A

study of the r a t e s of d e s o r p t i o n of W and Ta from MnO^ by means of

1% NaF s o l u t i o n s was made.

D i s t i l l a t i o n Generator. I r r a d i a t e d tantalum f o i l s were d i s s o l v e d i n HF + mOy the s o l u t i o n converted to 29N HF and heated to b o i l i n g i n an a l l - T e f l o n d i s t i l l a t i o n apparatus. Nitrogen was used as a c a r r i e r - g a s to d i s t i l (W-178) WF^ which could be used to generate the n o n - v o l a t i l e (Ta-178)TaF,_.

T h i s would then be

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch010

i s o l a t e d by vacuum manipulation of the WF^. Further E v a l u a t i o n of the E x i s t i n g Ta-178 Generator. Shielded Ta-178 generators of 2 cc bed s i z e that can be e l u t e d i n a short time by means of vacuum a s p i r a t i o n were prepared i n the Squibb M i n i t e c c o n f i g u r a t i o n . Generators were b u i l t u s i n g Bio-Rad AGlx8 as the adsorbent. The e f f e c t s of eluent a c i d i t y and hydrogen peroxide c o n c e n t r a t i o n , a u t o c l a v i n g , column bed s i z e v a r i a t i o n , t o t a l eluent volume used and eluent a d d i t i v e s on the breakthrough of W-178 and the y i e l d of Ta-178 were evaluated. The e l u a t e was analyzed f o r p o s s i b l e organic r e s i n - d e g r a d a t i o n products by means of gas-chromatography. In order to q u a n t i t a t i v e l y evaluate the presence and magnitude of the impurity i n s u c c e s s i v e e l u t i o n s , twelve " c o l d " standard columns were loaded with Bio-Rad AGlx8 r e s i n and subjected to a standard W-178-loading procedure, except that no W-178 was present i n s o l u t i o n . The e l u t i o n s were performed with 0.15 Ν HCl + 0.01% H ^ . At 1, 3, 11, and 38 days a f t e r p r e p a r a t i o n , three e l u t i o n s of 1 ml each were c o l l e c t e d from each column. The pH of the samples were adjusted to 12 as r e q u i r e d f o r the gas chromatography procedure. Q u a n t i t a t i o n was by flame i o n i z a t i o n a f t e r the gas chromatographic s e p a r a t i o n . Results The r e s u l t s of the Kp determinations are shown i n Tables I-IV. In Table I the data f o r systems that s t r o n g l y adsorbed both W and Ta are summarized. Table I I contains data on those systems which s t r o n g l y adsorb only Ta. In Table I I I the systems that p o o r l y adsorbed W are d e s c r i b e d . The e f f e c t of a c i d i t y on the adsorption of W and Ta onto a pyrogallol-formaldehyde c h e l a t e r e s i n i s summarized i n Table IV. The Kp values of W and Ta between s i l i c a or s i l y l a t e d s i l i c a and 1% NaF s o l u t i o n s of d i f f e r e n t pH values are summarized i n F i g u r e 1 ( l i n e s 3 and 3A). The Kp values f o r the same adsorbents but u s i n g d i f f e r e n t concentrations of HCl i n the eluent are summarized i n Table V.

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

156

RADIONUCLIDE

GENERATORS

T a b l e I . Kp V a l u e s f o r W a n d T a B e t w e e n V a r i o u s E l u e n t s and I n o r g a n i c A d s o r b e n t s w i t h a H i g h A f f i n i t y f o r Both Elements

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch010

Adsorbent/ Eluent Ti0 .H^0 2

*DTa Fe 0 /^)W 3

^Ta S b

T

22 ° S

/ K

H 0

0.1N NaOH

0.25% P04

0.9% NaCl

>2500

>500

59

>1300

>1300

>1000

>200

>400

>140

>300

>350

>300

>2400 >500

>1000 >250

>125 >125

>800 >200

>800 >170

>600 >200

>900 >200

>800 >200

o

0.1% NaHSO

2

DW

2

10 Ν HCl

DW

>250 >100

DTa MnO

A w *DTa

2100 >350

95 >200

800 >300

5600 >800

275 >150

140 >110

380 >200

1100 >200

1500

125

470

800

>140

>140

>90

>60

Ti-phosph/ W Ta Fe(lll)/ ferrocy/ iW Ta ZrO

/K

2 DW Ta

>100

>400

>250

>250

>200

>100

>50

>50

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

10.

NEIRINCKX ET AL.

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch010

Table I I .

the Ta-178

157

Generator

K^ of Tantalum Between Various Eluents and Inorganic Adsorbents with a High A f f i n i t y f o r Tantalum

3

1θ" Ν HCl

0.1N NaOH

0.25% P0.34

0.9% NaCl

0.1% NaHS0

TiO SnO^CCaCip

>200 >200

>30 >40

>60 >200

>150 >250

>300

>60

>70

Zr(ferrocy)

>250

>50

Ni(ferrocy)

>200

>70

Ti(ferrocy) K-Co(ferrocy)

>300 >300 >100

>90 >180

3

10" N HCl

SnO SiO^ Neutral A l 0 Cr0 Zr-phosph Sn-phosph Tungsten Carbide Phomix Siphozir Cr-phosph Cu-ferrocy MoO«(ferrocy) TiO, A l 6 /CaF o

2

3

2

3 0

>100

K^ Values of W Between Various Eluents and Inorganic Adsorbents with Low A f f i n i t y f o r Tungsten

Adsorbent/ Mobile Phase

2 3

for

Absorbent/ Mobile Phase

Table I I I .

ws

Adsorbents

o

3

30 27 30 2 15 4

H 0 2

68

44 14

5 34 53 3 8 7 95 3 6

110

0.1N NaOH

0.25% P0.34

0.7% NaCl +0.2% NaHC0

3

0.9% NaCl

0.1% NaHSO,

120 3

18

6

5

8 3 89 51

55 28

3 96 78

55 35

1 17 12 4 10

36

6

12

24

10 3 8 2

17 6 15 24

41 7 6 2 16 8

21 28 20 2

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

6

RADIONUCLIDE GENERATORS

Table IV.

^ o f W and T a Between P-F R e s i n and H C l S o l u t i o n s

- l o g Ν(HCl)

h'

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch010

Adsorption

1 2 3 4

T a b l e V.

W Adsorption

Desorption

210 310 200 220

2,500 3,250 3,900 2,850

285 420 490 350

2,000 2,000 2,000 2,000

o f W and T a Between S i l i c a o r S i l y l a t e d and Aqueous D i l u t e H C l

V

- l o g Ν(HCl)

Adsorption

Silylated 650 19 28

Silica

Ta

W

Adsorption Desorption

1 2 3

Desorption

Desorption

silica

>5,000 130 16

>500 >500 >20

>500 >100 >10

>20 >20 >20

>200 >500 >1,000

Silica 1 2 3

26 30 56

450 850 >5,000

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

Adsorbents

for the Ta-178

Generator

159

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch010

NEIRINCKX ETAL.

Figure 1. D i s t r i b u t i o n c o e f f i c i e n t s (K ) of W and Ta between SrF2, s i l y l a t e d Si02 or S1O2 and aqueous NaF s o l u t i o n s as a f u n c t i o n of the pH of the mobile phase. D

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

160

RADIONUCLIDE GENERATORS

The r e s u l t s of the a d s o r p t i o n experiments u s i n g Bio-Rad AGlx8 with the W-phosphotungstate were negative because stronger Ta-adsorption occurred w i t h these phosphate-containing s o l u t i o n s . The r e s u l t s of the Kp determination f o r W and Ta between Bio-Rad AGl-x4 and HCl s o l u t i o n s of d i f f e r e n t normality are summarized i n F i g u r e 2. The e f f e c t of the a d d i t i o n of ^PO^, to the 0.1 Ν HCl mobile phase i s a l s o i n d i c a t e d .

The r e s u l t s of the Kp

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch010

determinations f o r W and Ta between Chelex 100 and d i l u t e HCl s o l u t i o n s are shown i n Table VI. The r e s u l t s f o r Chelex 100 using 1% NaF s o l u t i o n s of v a r y i n g pH are summarized i n Table V I I . The Kp of W and Ta between MnO^ and aqueous s o l u t i o n s of d i f f e r i n g NaF concentrations and pH are summarized i n F i g u r e 3. The Kp values f o r W and Ta between Titanium phosphate and e i t h e r 1% NaF or 0.1% NaF Table V I I I .

s o l u t i o n s as a f u n c t i o n of pH are shown i n

The Kp values as a f u n c t i o n of pH f o r W and Ta

between SrF^ and 0.1% NaF ( l i n e s 1 and 1A). Si0

2

s o l u t i o n s are summarized i n F i g u r e 1

In F i g u r e 1 the Kp values of W and Ta between

( l i n e s 2 and 3A) or s i l y l a t e d S i 0

2

( l i n e s 2 and 2A) and

1%

NaF

s o l u t i o n s as a f u n c t i o n of pH are summarized. The r e s u l t s of the determination of the adsorption r a t e s of W and Ta onto Z r 0 and Mn0 are shown i n F i g u r e 4. L i n e s 1 and 2 2

2

show the a d s o r p t i o n of W and Ta onto Mn0

2

from 1% NaF

L i n e s 3 and 4 d e p i c t the adsorption of W and Ta by Z r 0 0.1%

sodium oxalate s o l u t i o n .

solutions. 2

from a

L i n e s 5 and 6 of F i g u r e 4 show

the d e s o r p t i o n of W and Ta from Mn0

2

by 1% NaF s o l u t i o n s .

Using

the M i n i t e c c o n f i g u r a t i o n , a f u l l bolus of Ta-178 was e l u t e d from the 2 cc Bio-Rad AGl-x8 columns by means of 1.5 ml of HCl 0.15 Ν + 0.01% Η 0 · The e l u t i o n i s performed with an evacuated v i a l 2

2

and takes only 15 seconds. The adsorbent bed can be l e f t dry between e l u t i o n s . In the d i s t i l l a t i o n experiment, (W-178)WF could not be 6

d i s t i l l e d from the 29 Ν HF s o l u t i o n s , using the a l l - T e f l o n d i s t i l l a t i o n apparatus. The e l u t i o n y i e l d f o r Ta-178 from Bio-Rad AGl-x8 by means of 1.5 ml of 0.10 Ν HCl + 0.01% H ^ or 1.5 ml of 0.15 Ν HCl + 0.01% H 0 2

2

was

33% and 52%, r e s p e c t i v e l y .

breakthrough

The Ta-178 y i e l d s and

values obtained with 2 ml of 0.15

v a r i a b l e amounts of H 0 o

o

are shown i n Table IX.

W-178

Ν HCl c o n t a i n i n g Table X shows

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch010

10.

NEIRINCKX ET AL.

Adsorbents

for

the Ta-178

αΟΙ 0J03

161

Generator

O.IO

Ν HCL F i g u r e 2. D i s t r i b u t i o n c o e f f i c i e n t s ( Κ ) o f W and Ta b e ­ tween B i o - R a d A G l x 4 and aqueous H C l s o l u t i o n s a s a f u n c t i o n of H C l c o n c e n t r a t i o n . β

Table V I .

Kp o f W and T a Between C h e l e x 100 and M o b i l e Phases o f V a r y i n g H C l C o n c e n t r a t i o n (10 Desorption) f

_

pH

W

0.6 0.8 1.0 1.1 1.3 4.8 9.0

950 1,250 3,000 3,000 4,000 75 10 10

Ta 100 150 400 500 40 10 20

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

162

RADIONUCLIDE

Table V I I . ^

GENERATORS

o f W and T a Between C h e l e x 100 and 1% NaF Aqueous S o l u t i o n s a s a f u n c t i o n o f pH (10 desorption)

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch010

f

pH

W

1.8 2.0 3.1 3.9 5.1 6.0 7.4 8.3 8.7 9.9

1,600 300 350

Ta 85 100 80 90 40 50 25 20 10 2

-130 170 30 20 10 1

ΒL o f W and T a Between T i - p h o s p h a t e and fi l u o r i d e s o l u t i o n s a s a f u n c t i o n o f pH

Table V I I I .

0.1% NaF

1% NaF pH

pH W

0.4 0.8 1.3 1.6 2.1 4.0 5.4 6.0 6.4 6.6

42 150 90 270 320 760 920 1,900 530 460

W

Ta 22 50 70 150 200 140 120 170 370 >500

1.1 1.5 2.0 3.0 3.4 4.3 4.7 5.0 5.1 5.2

230 890 360 420 450 780 1,250 1,450 1,100 1,100

Ta >250 410 175 160 160 200 340 340 320 330

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

Adsorbents

NEIRINCKX ET AL.

for

the Ta-178

Generator

IQOOO

1000

Ι­

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch010

ο

100 γ­

ΙΟ

4 -PH-

Figure 3. D i s t r i b u t i o n c o e f f i c i e n t s ( K ) of W and Ta be­ tween Mn0 and aqueous NaF s o l u t i o n s of d i f f e r e n t concen­ t r a t i o n as a f u n c t i o n of the pH of the mobile phase. D

2

1,000

\////////////////////^^ (5) W- desorption M n 0

2

ο 100

(2) Τα-adsorption

Mn0

2

10

f

-L 10'

-L 30' Time of equilibration

60'

Figure 4. Adsorption r a t e of W and Ta onto Mn02 and Zr02 from aqueous 1% NaF s o l u t i o n s and desorption of these elements from MnOo.

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

164

RADIONUCLIDE GENERATORS

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch010

the i n f l u e n c e of a u t o c l a v i n g of the loaded AGl-x8 generator on the Ta-178 y i e l d and radiochemical p u r i t y (RCP)· To i n h i b i t the m i g r a t i o n of p a r t i c l e s during the a u t o c l a v i n g , an intermediary f i l t e r was added 5 mm under the top f i l t e r of the column. The e f f e c t of a u t o c l a v i n g on the Ta-178 y i e l d and RCP f o r t h i s type of column i s summarized i n Table XI. The r e s u l t s of an exhaustive e l u t i o n of a 1 cc Ta-178 generator based on Bio-Rad AGlx8 i s shown i n Table X I I . Each e l u t i o n was performed with 1 ml of HCl 0.15N + 0.01% H ^ . Several mixtures of 0.15 Ν HCl with other components were evaluated as eluents f o r a 2 cc Ta-178 generator. The r e s u l t s are summarized i n Table X I I I . Trimethylamine was i d e n t i f i e d as a product of the decomposition of the Bio-Rad AGl-x8 anion-exchange r e s i n . The q u a n t i t a t i v e r e s u l t s obtained by gas-chromatography and FID are summarized i n Table XIV. Discussion Using a 0.10

Ν HCl + 0.01%

H ^

as e l u e n t , the L i f e Sciences

D i v i s i o n of the N a t i o n a l Aeronautics and Space A d m i n i s t r a t i o n (NASA) has s u c c e s s f u l l y operated a l a r g e number of Ta-178 generators based on Bio-Rad AGlx8 and has s u c c e s s f u l l y t e s t e d them i n human s u b j e c t s 05). U l t i m a t e l y , t h e i r i n t e n t i o n i s to use these f o r e v a l u a t i o n of c a r d i a c f u n c t i o n of astronauts i n space. The only published Ta-178 generator i s based on adsorption of W-178 on an organic anion-exchanger and e l u t i o n of the daughter i s o t o p e by means of a d i l u t e HCl e l u e n t , c o n t a i n i n g a small amount of H^O^. The e l u a t e can e a s i l y be converted to an i n j e c t a b l e s o l u t i o n and the Ta-178 y i e l d s i n 1 ml eluent volume are higher than 50%. However, the W-breakthrough i n c r e a s e s to more than 0.1% a f t e r about 50 c o l l e c t i o n s . The e a r l y breakthrough and the r a d i o l y t i c i n s t a b i l i t y of organic adsorbents are the main drawbacks of t h i s system. An attempt to c o r r e c t these shortcomings by u s i n g a more r a d i a t i o n - r e s i s t a n t i n o r g a n i c adsorber or with any other adsorbent that would adsorb W more s t r o n g l y than Bio-Rad AGlx8 d i d not lead to a procedure that was s u p e r i o r to the o r i g i n a l system. Many i n o r g a n i c adsorbents have a high a f f i n i t y f o r tungsten but t y p i c a l l y a l s o adsorb tantalum very s t r o n g l y . I t was noted that Ta-178 which had grown i n from W-178 while the l a t t e r was adsorbed was very s t r o n g l y r e t a i n e d by a l l the i n o r g a n i c adsorbents. The reason f o r t h i s strong Ta b i n d i n g may r e s u l t from i s o e l e c t r o n i c t r a n s i t i o n of the W-178 which probably does cleave any chemical bonds between the daughter isotope Ta-178 and the atoms or groups of the molecule. 2Since most of the experiments have been performed with WO^ , the r e s u l t a n t Ta species may be expected to remain oxygenated because Ta 5 d - o r b i t a l s overlap s t r o n g l y with oxygen 2 p - o r b i t a l s to give s u b s t a n t i a l ^-bonding.

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

Adsorbents

NEIRINCKX ET AL.

for the Ta-178

165

Generator

Table IX. Ta-178 Y i e l d and W-178 Breakthrough from Bio-Rad AGlx8 as a Function of the H 0 -Concentration 0

% H 0

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch010

2

0

W-178 Breakthrough

Ta-178 Y i e l d

2

(%)

J

(xio ) 5 0.2 N.A. A g " ^ [ 2 . 2 . 2 ] , and t h u s [ A g ] = k [Ag(2.2.2)]. A c r i t i c a l t e s t o f t h i s m o d e l i s how a c c u r ­ a t e l y i t p r e d i c t s the i n f l e c t i o n p o i n t i n the c l e a r a n c e +

+

d

curve. The b e s t f i t o c c u r r e d f o r a o f 2 χ 10 sec , in agreement w i t h t h e l i t e r a t u r e v a l u e f o r k (cf Figure 2). d

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

RADIONUCLIDE GENERATORS

208

water. There was no evidence f o r a c c e l e r a t e d d i s s o c i a t i o n i n the i n t r a v a s c u l a r space. Results with Sr" "[2.2.2] i n Mice. While the r e s u l t s with Ag crypt a t e were encouraging, we sought f u r t h e r p r e l i m i n a r y evidence of the p o t e n t i a l value of l a b e l e d cryptâtes as blood-flow radiopharmaceuticals. There were s e v e r a l reasons f o r these s t u d i e s : the monovalent s i l v e r i o n i s very p o l a r i z a b l e and thus may not be a general model f o r monovalent c a t i o n s (5,17). In c o n t r a s t , d i v a l e n t c a t i o n s form stronger i n c l u s i v e cryptâtes than monovalent c a t i o n s of the same i o n i c r a d i i . On the other hand, the added charge of the d i v a l e n t i o n would r e q u i r e that the cryptand s h i e l d more charge i f i t i s to r e s u l t i n an e q u a l l y l i p o p h i l i c complex. The above c o n s i d e r a t i o n s l e d us to i n i t i a t e work with Sr-85 as a t r a c e r f o r cryptand [ 2 . 2 . 2 ] . Strontium-85 decays with emission of a 514 keV gamma, i s commercially a v a i l a b l e and has a convenient -5 -4 h a l f - l i f e (T^ = 65d). The l i t e r a t u r e value f o r k , 0.75 χ 10 sec \ i s about 5-25 f o l d slower than the value f o r A g (13). The i o n i c r a d i i of monovalent Ag and d i v a l e n t Sr are equal to or s l i g h t l y l e s s than the i n t e r n a l diameter of the [ 2 . 2 . 2 ] cryptand. Mouse d i s t r i b u t i o n experiments were performed with Sr" "[2.2.2] f o l l o w i n g the p r o t o c o l developed f o r Ag c r y p t a t e , except that measurements were done at only 1 and 15 minutes a f t e r i n j e c t i o n . The r e s u l t s are shown i n Figure 6 as % ID i n each organ and are graphed and keyed to allow d i r e c t comparison with the A g [ 2 . 2 . 2 ] data. The comparative data with S r C l ^ at 15 minutes are a l s o

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch014

H

d

+

H

+

shown. F i g u r e 7 summarizes the l i m i t e d blood clearance data f o r S r " ' [ 2 . 2 . 2 ] and S r C l . H

2

Several a d d i t i o n a l conclusions can be made from these r e s u l t s . The e a r l y data f o r both c r y p t a t e l a b e l s were s i m i l a r f o r muscle, kidney, lung, spleen, and gut; whereas the accumulation of Sr"* [ 2 . 2 . 2 ] was 3-5 f o l d lower than Ag+[2.2.2] i n the l i v e r , heart, and b r a i n . There were more d i f f e r e n c e s between the r e s u l t s a t 15 minutes s i n c e muscle and kidney concentrations were s i m i l a r f o r both l a b e l s , but the strontium c o n c e n t r a t i o n was much lower i n the remainder of the organs. Although the number of measure­ ments i s l i m i t e d , the slopes o f the organ concentrations between 1 and 15 minutes appear r e l a t i v e l y constant f o r both radiophar­ maceuticals and most of the organs s t u d i e d . The amount i n the kidneys f o r Sr and the gut f o r Ag appear d i f f e r e n t . The c o n t r o l experiments with S r C l ^ showed a d i s t r i b u t i o n that -1-

was q u a l i t a t i v e l y d i f f e r e n t from that of the c r y p t a t e . The d i s ­ t r i b u t i o n of S r C l at 15 minutes was more l i k e the d i s t r i b u t i o n 2

of g a l l i u m c i t r a t e at 60 minutes shown i n F i g u r e 3. These data seem to i n d i c a t e that the e a r l y S r C l d i s t r i b u t i o n patterns are 2

probably i n d i c a t i v e of a plasma space, and that the Sr c r y p t a t e i s

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

14.

Cryptate

KROHNETAL.

"i

Complexes

209

Γ

+ +

Sr C2.2.2]

Ψ

Ο à

Ν

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch014

\





\ \

f

•\

Δ

V

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I

\

\

\

V

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\

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I

L

I IONIC Sr C l

15

TIME

Figure

6.

tissues chloride

Tissue

of mice. a t 15

Livtr Δ Out Ο Heart •

• I

2

,



S f 15

Brain f IONIC S r C I

2

(min)

distribution Comparison

of

data

++ Sr

[2.2.2]

are given

i n various

f o r Sr

as

min.

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

the

210

GENERATORS

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch014

RADIONUCLIDE

+ +

F i g u r e 7. The b l o o d c l e a r a n c e o f S r [ 2 . 2 . 2 ] was a l s o b i phasic but c l e a r l y e x h i b i t e d a lower i n t e r c e p t f o r the slowc l e a r i n g component.

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

KROHNETAL.

14.

Cryptate

Complexes

211

not d i s s o c i a t i n g instantaneously a f t e r i n j e c t i o n . I f t h i s were the case, the d i s t r i b u t i o n s o f Sr c r y p t a t e and of i o n i c strontium would be s i m i l a r a t 15 minutes. When the organ d i s t r i b u t i o n s were p l o t t e d as the organ/blood r a t i o s (graphs not shown), the d i f f e r e n c e s between Ag and Sr became more apparent. The measurements f o r S r [ 2 . 2 . 2 ] were much more constant with time than were the r a t i o s f o r A g [ 2 . 2 . 2 ] . This r e s u l t i s c o n s i s t e n t with Sr++ forming a stronger complex than Ag , so that the i n t a c t complex experiences r a p i d exchange between the organ and v a s c u l a r spaces. This property would be r e q u i r e d f o r an i n e r t and f r e e l y d i f f u s i b l e t r a c e r . The blood clearance curve (Figure 7) a l s o suggests that S r [ 2 . 2 . 2 ] i s a more s t a b l e complex than i t s Ag counterpart. In the case o f Sr, about 95% o f the t r a c e r c l e a r e d with a f a s t h a l f - l i f e , compared w i t h about 85% f o r Ag. When the blood clearance was simulated as i l l u s t r a t e d i n -4 -1 Figure 5b, we estimated a k, o f about 3 χ 10 sec f o r the Sr -3 - l l a b e l versus 2 χ 10 sec f o r Ag. + +

+

+

Publication Date: January 30, 1984 | doi: 10.1021/bk-1984-0241.ch014

+ +

d

Summary and Conclusions The mouse d i s t r i b u t i o n experiments i n d i c a t e d a great deal o f s i m i l a r i t y between the A g and the Sr"*" cryptâtes, g i v i n g us confidence that the cryptand l i g a n d was i n f l u e n c i n g , i f not completely dominating, the b i o d i s t r i b u t i o n of both radiopharmaceuticals. There were, however, d i s t i n c t d i f f e r e n c e s between these l a b e l s that were c o n s i s t e n t with our p r e d i c t i o n s that the Sr" " l a b e l would be more s t a b l e i n v i v o but a l s o l e s s l i p o p h i l i c because of i t s increased charge. Blood clearance measurements showed l e s s i n v i v o breakdown f o r Sr, with subsequent l a b e l i n g of the plasma space. Accumulation o f t r a c e r Sr-85 i n the s k e l e t o n was i n s u f f i c i e n t to account f o r t h i s d i f f e r e n c e . While these would be advantages f o r the Sr l a b e l , the o b s e r v a t i o n that Sr"*"* [ 2 . 2 . 2 ] was not detected i n the b r a i n , heart, and l i v e r as much as the c r y p t a t e l a b e l e d with monovalent Ag, emphasizes the problem that a Sr""*" c r y p t a t e i s s u f f i c i e n t l y l e s s l i p o p h i l i c so that i t s d i s t r i b u t i o n i s a f f e c t e d by the higher charge on the c e n t r a l capt i o n . These r e s u l t s support the p o t e n t i a l o f cryptands f o r making i n e r t , f r e e l y d i f f u s i b l e complexes with generator-produced r a d i o n u c l i d e s . With the present data, we a r e unable to p r e d i c t whether monovalent or d i v a l e n t c a t i o n s would be more advantageous l a b e l s . Other cryptands can be synthesized to g i v e c a v i t i e s w i t h more f a v o r a b l e i n t e r n a l dimensions than those that a r e commercially a v a i l a b l e (4). We e n v i s i o n s e v e r a l p o t e n t i a l generator-produced r a d i o n u c l i d e l a b e l s f o r cryptâtes (Table I ) . F o r t u n a t e l y , e a r l y e v a l u a t i o n s can be performed more conveniently with l o n g e r - l i v e d t r a c e r s that are commercially a v a i l a b l e . The c r y p t a t e complexes a r e convenientl y formed from the metal i n d e i o n i z e d water and the cryptand d i s s o l v e d i n water o r methanol. The complexes form i n s t a n t l y upon +

1-

H

1

In Radionuclide Generators; Knapp, F., el al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

212

RADIONUCLIDE

μ ω

α) CO ο ω β

ω ΓΗ

Ο

Ρ

cd

+

Ρ

rH

CM

+

+

GENERATORS

CM

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