Au-195m Generator for

3 Preparation and Characteristics of a Hg-195m/Au-195m Generator for First-Pass Angiography

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R. B E T T , J. G. CUNINGHAME, H . E . SIMS, and H. H. W I L L I S — A t o m i c Research Establishment, H a r w e l l , Oxfordshire, ΟΧ11 0RA, England

Energy

D . S. DYMOND, W. FLATMAN, and D . L . S T O N E — S t . Bartholomew's Hospital, West Smithfield, L o n d o n EC1A 7 B E , England A . T . E L L I O T T — W e s t e r n Infirmary, Glasgow, G11 6 N T , Scotland

A Hg-195m/Au-195m generator has been developed f o r medical use i n first pass heart angiography. The mercury parent i s bound to a t h i o l - c o n t a i n i n g column m a t e r i a l from which Au-195m i s eluted i n d i l u t e sodium cyanide s o l u t i o n . Such generators may have l a r g e q u a n t i t i e s of a c t i v i t y adsorbed on the column and t h i s can r e s u l t i n r a d i o l y t i c r e a c t i o n s which cause a decrease of e l u t i o n e f f i c i e n c y with time. C a r e f u l timing of the various operations involved i n preparing these generators can help to stop this deterioration. Gold-195m decays to Au-195 which has a half-life of 183 days and i t i s important to operate the generator i n such way as to keep the amount of Au-195 i n j e c t e d i n t o the p a t i e n t to a minimum. The method of production of these generators i s presented. E f f e c t s of radiolytic r e a c t i o n s on generator use, and i m p l i c a t i o n s of the mass 195 decay chain to u l t i m a t e p u r i t y of the product are discussed. F i r s t pass r a d i o n u c l i d e angiography of the heart involves the i n j e c t i o n of a small bolus of r a d i o a c t i v i t y i n t o a p e r i p h e r a l v e i n , and imaging the bolus as i t passes through the heart. In recent years the q u a n t i t a t i v e measurement of c a r d i a c f u n c t i o n with t h i s technique has become c l i n i c a l l y u s e f u l i n the assessment of c a r d i a c disease (I). A major strength of the method i s the a b i l i t y to study c a r d i a c physiology non-invasively under s t r e s s such as e x e r c i s e , an approach which i s d i a g n o s t i c a l l y u s e f u l p a r t i c u l a r l y i n p a t i e n t s with coronary a r t e r y disease. A major drawback with the method i s the requirement of a separate i n j e c t i o n of the r a d i o n u c l i d e f o r each study. U n t i l r e c e n t l y the only a v a i l a b l e isotope f o r such studies has been Tc-99m, but i t s r e l a t i v e l y long h a l f - l i f e (6 hours), along with the amount of a c t i v i t y required f o r each study (>10mCi), has precluded more than two i n j e c t i o n s per s e s s i o n because of p a t i e n t dose and degradation of p i c t u r e s by background a c t i v i t y i n the blood pool. These r e s t r i c t i o n s have 0097-6156/ 84/ 0241 - 0 0 3 5 5 0 6 . 0 0 / 0 P u b l i s h e d 1984 A m e r i c a n C h e m i c a l S o c i e t y

Knapp and Butler; Radionuclide Generators ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

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prevented s i m i l a r s t u d i e s being c a r r i e d out on p a e d i a t r i c p a t i e n t s where they could be used to i d e n t i f y v a l v e d i s o r d e r s e t c . , s i n c e they would r e c e i v e too high a dose. For the f u l l p o t e n t i a l of the technique to be r e a l i z e d a short l i v e d isotope was required which would by n e c e s s i t y be the daughter of a l o n g - l i v e d parent, together making a generator p a i r . Two such generator p a i r s have been p r e v i o u s l y reported: Rb-81/Kr-81m (2) and Os-191/lr-191m ( 3 ) , however n e i t h e r i s s u i t a b l e since Kr-81m i s e l i m i n a t e d from blood on passage through the lungs, and the h a l f - l i f e of Ir-191m (5 sees) i s too short to permit adequate study of the l e f t h e a r t . However Lebowitz (4) noted the p o s s i b i l i t i e s of the Hg-195m/Au-195m p a i r and we have already described our p r e l i m i n a r y r e s u l t s (5,6) using t h i s system. Another Hg-195m/Au-195m generator i s a l s o i n c l i n i c a l use (7)· One based on a Chelex-100 r e s i n has been reported ( 8 ) , but no i n d i c a t i o n of a c t i v i t y on the column nor i n s o l u t i o n was given. The c h a r a c t e r i s t i c s f o r an i d e a l generator p a i r f o r f i r s t pass angiography and those of the Hg-195m/Au-195m generator described here are shown i n Table I . The energy of the p r i n c i p a l γ-ray

Table I . P h y s i c a l Requirements of a Generator P a i r f o r F i r s t Angiography Property Parent h a l f - l i f e Daughter h a l f - l i f e P r i n c i p a l γ-ray Abundance

Ideal

Generator

> 24 h < 1 min 100-300 keV 100%

Pass

Hg-195m/Au-195m 41 h 30.5 sec 262 keV 67%

(262 keV) i s a l i t t l e high and the abundance lower than i d e a l , but t h i s system i s nevertheless q u i t e adequate. Operating requirements of a generator f o r the f i r s t pass angiography are shown i n Table II. In p r a c t i c e the generator i s l i k e l y to be based on a chromatographic column because of the short time a v a i l a b l e f o r anything other than a s t r a i g h t e l u t i o n stage. The remainder of t h i s paper d e s c r i b e s the p r e p a r a t i o n and p r o p e r t i e s of such a generator with s p e c i a l reference to breakthrough and u l t i m a t e daughter i m p u r i t i e s . Experimental Production of Hg-195m. Gold i s monoisotopic and the most convenient method f o r p r e p a r a t i o n of Hg-195m i s by the Au-197(p,3n) Hg-195m r e a c t i o n . We i r r a d i a t e m e t a l l i c gold t a r g e t s 0.5mm t h i c k with 34 MeV protons. About 8 MeV i s absorbed i n the t a r g e t , g i v i n g a p r a c t i c a l y i e l d of about 4 mCi/yA/hr at end of bombardment. Good cooling i s e s s e n t i a l to prevent l o s s of product during the


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i r r a d i a t i o n because of the v o l a t i l i t y of mercury. Mercury-195m i s then separated from the gold target by p l a c i n g i n a furnace at 1000°C i n a helium gas flow (50 ml/min) f o r 1 hour. The evaporated mercury i s c o l l e c t e d i n 20 ml of n i t r i c a c i d (10%) and then buffered with sodium acetate (5 g ) .

Table I I .

a) b) c) d) e) f) 8) b)

Operating Requirements of a Generator f o r F i r s t Angiography

Pass

Fast daughter/parent s e p a r a t i o n Daughter obtainable i n good y i e l d Daughter a c t i v i t y 10-20 mCi i n 0.5 ml Low parent breakthrough Stable against r a d i a t i o n damage Daughter a c t i v i t y i n non-toxic, pyrogen-free, sterile solution Robust f o r transport Easy to use

Column Adsorption of Hg-195m. P r e l i m i n a r y work and a review of the l i t e r a t u r e showed that conventional i o n exchangers would not e f f e c t the s e p a r a t i o n of mercury and gold and that the best method would be to use an i o n exchange m a t e r i a l where the a c t i v e species was a thiol group (9)· The first material used was vicinal d i t h i o c e l l u l o s e (10), which has been described p r e v i o u s l y ( 5 ) . This m a t e r i a l had s e v e r a l disadvantages: i t i s not commercially a v a i l a b l e , i t has high s u s c e p t i b i l i t y to r a d i a t i o n damage and poor flow c h a r a c t e r i s t i c s . Two a d d i t i o n a l commercially a v a i l a b l e t h i o l c o n t a i n i n g m a t e r i a l s were i n v e s t i g a t e d and subsequently used i n patient t r i a l s : they were t h i o p r o p y l sepharose-6B (Pharmacia Chemicals, Ltd.) and c o n t r o l l e d pore g l a s s (CPG) lipoamide ( P i e r c e Chemical Co. L t d . ) . These m a t e r i a l s were prepared f o r use by washing with e t h y l e n e - d i a m i n e - t e t r a a c e t i c acid/sodium acetate s o l u t i o n to c h e l a t e any heavy i o n s . T h i s treatment a l s o serves as a s w e l l i n g s o l u t i o n f o r the sepharose m a t e r i a l . The m a t e r i a l was then reduced with mercapto-acetic a c i d f o r about 1 hour to produce f r e e t h i o l groups and then washed s e v e r a l times with a c e t i c acid/sodium c h l o r i d e s o l u t i o n . Mercury-195m was then bound to the column m a t e r i a l by mixing with the a c t i v e s o l u t i o n and s t i r r i n g by bubbling a slow gas flow through the s o l u t i o n f o r about 30 minutes. Mechanical s t i r r i n g was found to i n c r e a s e parent breakthrough probably as a r e s u l t of mechanical damage to the m a t e r i a l r e s u l t i n g i n small fragments passing through i n t o the e l u a t e . The m a t e r i a l was then drawn onto the column and washed with about 50 ml of sodium cyanide (2.5 mM). Another m a t e r i a l , E n z a c r y l p o l y t h i o l (Koch L i g h t L t d . ) , was a l s o i n v e s t i g a t e d . This i s a polymeric m a t e r i a l which binds Hg very w e l l , but undergoes radiolytic r e a c t i o n s turning i t i n t o a g e l , which completely stops the


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passage of eluant through the m a t e r i a l . I t was found that drawing the a c t i v e s o l u t i o n through the column m a t e r i a l was a l s o an e x c e l l e n t way of binding the mercury, except that i t adsorbed i n a very narrow band of extremely high " s p e c i f i c a c t i v i t y " ( " s p e c i f i c a c t i v i t y " i s used here as a measure of a c t i v i t y per mg of column m a t e r i a l ) which resulted i n radiolytic r e a c t i o n s , causing a dramatic drop i n e l u t i o n e f f i c i e n c y . Discussion Column Performance. The only eluant found to e l u t e Au-195m i n any reasonable yield was NaCN, consequently the m a t e r i a l s were i n v e s t i g a t e d f o r v a r i a t i o n i n e l u t i o n e f f i c i e n c y as a f u n c t i o n of s e v e r a l v a r i a b l e s , namely, c o n c e n t r a t i o n of cyanide, the volume of cyanide, and t i m e / " s p e c i f i c a c t i v i t y " of Hg-195m on column. These parameters were of p a r t i c u l a r importance because of the o v e r - r i d i n g requirement that the s p e c i f i c a c t i v i t y of Au-195m i n s o l u t i o n should be greater than 20 mCi/ml. The parameter used to compare r e s u l t s was the % e l u t i o n e f f i c i e n c y where: % elution efficiency -

J ^ L S '

The e f f e c t of cyanide c o n c e n t r a t i o n i s shown i n Figure 1. In order to keep the c o n c e n t r a t i o n of cyanide as low as p o s s i b l e , 2.5 mM was chosen f o r subsequent t e s t s . Obviously higher e f f i c i e n c i e s could be obtained with 10 mM cyanide - t h i s would s t i l l be non-toxic under the c l i n i c a l c o n d i t i o n s used. Figure 2 shows the e f f e c t of v a r y i n g cyanide volume on e l u t i o n e f f i c i e n c y ; c l e a r l y the smaller the volume of eluant the lower the e l u t i o n e f f i c i e n c y . Conversely, the smaller the column the greater the e f f i c i e n c y , but a l l columns were >20% e f f i c i e n t with 0.6 ml of e l u a n t . The volume of column material i s controlled by the t h i r d parameter, that Is the v a r i a t i o n i n e l u t i o n e f f i c i e n c y with time f o r various " s p e c i f i c a c t i v i t i e s " of Hg-195m. I d e a l l y there should be no v a r i a t i o n i n e l u t i o n e f f i c i e n c y with time. The e f f e c t of varying " s p e c i f i c a c t i v i t y " i s shown i n Figures 3 and 4. These graphs show that at high " s p e c i f i c a c t i v i t i e s " , although the i n i t i a l e l u t i o n e f f i c i e n c y may be very high i t then drops, e s p e c i a l l y on standing overnight. This drop i n e l u t i o n e f f i c i e n c y was shown to be a r e s u l t of r a d i o l y t i c r e a c t i o n s by i r r a d i a t i n g low " s p e c i f i c a c t i v i t y " columns i n a Co-60 source. The r e s u l t s are shown i n Table I I I . This mechanism i s f u r t h e r confirmed by the suppression of damage by the use of r a d i c a l scavengers. Table IV shows the r a d i c a l and molecular products of water r a d i o l y s i s along with t h e i r r e l a t i v e y i e l d s f o r gamma rays (11). Some p o s s i b l e r e a c t i o n s which may be o c c u r r i n g a r e considered l a t e r i n t h i s paper. Any r a d i o n u c l i d i c impurity w i l l a l s o c o n t r i b u t e to t h i s damage and s i n c e Hg-195 i s produced d i r e c t l y during the i r r a d i a t i o n as w e l l as from the decay of Hg—195m (Figure 5), i t i s worth l e a v i n g the i r r a d i a t e d target f o r 10 to 20 hours before processing and loading the column.


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Time after activity absorbed on columns ( hours )

Figure 4. CPG Lipoamide Columns: Time dependence of e l u t i o n e f f i c i e n c y f o r d i f f e r e n t " s p e c i f i c a c t i v i t y " columns.


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Table I I I . E f f e c t of γ-Irradiation

Column I r r a d i a t e d f o r D i f f e r e n t Times

Experiment 1: Dose (M Rad)

on E l u t i o n E f f i c i e n c y

%

Hg-195m Breakthrough ( μ α per mCi Au-195m)

56 56 35 11

3.0 2.4 0.8 0.8

Elution Efficiency

0 0.16 3.2 13.4 Experiment 2:

Comparison

of Two I d e n t i c a l Columns

Dose

Efficiency

Breakthrough

Dose

Ef f i c i e n c y

Breakthrough

0 0 0 0 3.2

81 92 94 80 37

0.5 0.9 0.4 0.2 0.12

0 3.2 3.2 3.2 0

98 33 33 14 14

0.18 2.1 1.3* 0.8** 0.5

* Both columns eluted with 2% n i t r a t e / 2 . 5 mM cyanide ** Both columns eluted with 2.5 mM cyanide

Table IV: R a d i c a l and Molecular Products of Water R a d i o l y s i s Species 0Η· e" Η· H 0 H 2

2

2

No. formed per 100 eV absorbed 2.9 2.7 0.6 0.8 0.45

Breakthrough and Daughter A c t i v i t i e s . The i d e a l column would have no breakthrough and the daughter would decay to a s t a b l e product. These generators do have a l i t t l e breakthrough and Au-195m decays to Au-195 (see Figure 6) with a h a l f - l i f e of 183 days. On standing f o r any s i g n i f i c a n t length of time (>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


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Table V:

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.


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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. Knapp and Butler; Radionuclide Generators D. C. 20038 ACS Symposium Series;Washington, American Chemical Society: Washington, DC, 1984.

10use The and

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A c k n o w l e dgment s 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


Au-195m Generator for

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