Cryptate Complexes of Generator-Produced Isotopes - ACS

14 Cryptate Complexes of Generator-Produced Isotopes K. A .

KROHN

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D i v i s i o n o f Nuclear Medicine, R C - 7 0 , University of Washington, Seattle, W A 98195 Y. Y A N O , T. F.

BUDINGER,

and B. R.

MOYER

Department of Research Medicine, D o n n e r Laboratory, University of California, Berkeley, CA 94720

We report some p r e l i m i n a r y measurements of the p o t e n t i a l of m u l t i c y c l i c polyethers (cryptands) as l i g a n d s to modify the pharmacokinetic prope r t i e s of simple r a d i o a c t i v e ions a v a i l a b l e from generators. The i n vivo behavior o f the complexes (cryptates) should be dominated by the h i g h l y lipophilic surface of the cryptand which surrounds the charged r a d i o a c t i v e i o n . We e n v i s i o n c r y p t a t e complexes with s e v e r a l generator-produced isotopes but initiated our measurements with l o n g e r - l i v e d n u c l i d e s , i n c l u d i n g monovalent Ag-110m and d i v a l e n t Sr-85 bound to the [2.2.2] cryptand. Murine d i s t r i b u t i o n k i n e t i c s were s i m i l a r f o r both Ag and Sr l a b e l e d [2.2.2] , g i v i n g us confidence that the l i g a n d was dominating the b i o d i s t r i b u t i o n propert i e s of these complexes. At 1-2 min the c r y p t a t e d i s t r i b u t i o n s were a l s o s i m i l a r to blood flow expressed as a percentage of c a r d i a c output. There were two important d i f f e r e n c e s between the l a b e l s ; Sr was more s t a b l e i n v i v o but Ag was more lipophilic. These r e s u l t s suggest that generator -produced isotopes such as Rb-82 (T½ = 75 sec) sequestered i n s i d e cryptands may be u s e f u l f r e e l y diffusible t r a c e r s f o r measuring blood flow by p o s i t r o n emission tomography. I t would be more convenient to make t h i s measurement with generator-produced isotopes than with water from c y c l o t r o n -produced oxygen-15 (T½ = 122 s e c ) . The time course f o r b i o d i s t r i b u t i o n of a radiopharmaceutical throughout the body i s a m u l t i f a c e t e d f u n c t i o n i n v o l v i n g the r a t e of d e l i v e r y of the t r a c e r to i n d i v i d u a l t i s s u e s , the r a t e at which the t r a c e r i s extracted and r e t a i n e d by the t i s s u e s , and the r a t e at which the t r a c e r i s chemically processed, or f o r some reason egresses from the t i s s u e . In metabolic imaging 0097-6156/ 84/ 0241 -0199506.00/ 0 © 1984 American Chemical Society

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

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the goal i s to i n t e r p r e t pharmacokinetics i n terms of the second and t h i r d o f these f a c t o r s ; yet the f i r s t f a c t o r , that of d e l i v e r y of the t r a c e r to target t i s s u e s , w i l l always be a complicating f a c t o r i n modeling metabolic radiopharmaceuticals. For t h i s reason, p h y s i o l o g i c tomography using p o s i t r o n e m i t t i n g radiopharmaceuticals would b e n e f i t from independent measurements of blood flow to the t a r g e t t i s s u e . T h i s i n f o r m a t i o n would allow the i n v e s t i g a t o r to q u a n t i t a t i v e l y separate hemodynamic f a c t o r s from biochemical f a c t o r s when i n t e r p r e t i n g the time course of metabolic radiotracers. Simultaneous measurements o f flow and metabolism have been achieved using simultaneous i n j e c t i o n s of c o c k t a i l s c o n t a i n i n g t r i t i u m , carbon-14, i o d i n e - 1 2 5 and/or microspheres l a b e l e d with v a r i o u s n u c l i d e s . However, because a l l p o s i t r o n emitters i n v o l v e the same gamma energy f o r the detected r a d i a t i o n , i t i s not usef u l to simultaneously i n j e c t two d i f f e r e n t p o s i t r o n e m i t t i n g r a d i o chemicals, one p u r e l y a marker f o r blood flow, the other i n v o l v ing metabolism. The next best experimental approach would be to make the hemodynamic measurement i n the c l o s e s t p o s s i b l e temporal proximity to i n j e c t i o n of the biochemical t r a c e r . T h i s can be done best using the s h o r t e s t l i v e d r a d i o n u c l i d e s that are p r a c t i c a l f o r the measurement. Radionuclide generators are the i d e a l source f o r these i s o t o p e s . Thus we are developing t r a c e r s f o r measurement o f blood flow that are based on complexes of very s h o r t - l i v e d n u c l i d e s a v a i l a b l e from generators. Our i n i t i a l goal was to t e s t the p o t e n t i a l of c y c l i c p o l y ethers as m o d i f i e r s of the pharmacokinetics of simple r a d i o a c t i v e ions. Would they r e s u l t i n a l t e r e d b i o d i s t r i b u t i o n s that could be i n t e r p r e t e d as r e p r e s e n t a t i v e of blood flow? Simple macroc y c l i c organic l i g a n d s such as cyclam C O and the crown ethers (2) have been the subject of some i n v e s t i g a t i o n i n the f i e l d of nuc l e a r medicine. However, our e f f o r t s were d i r e c t e d toward the use of cryptands, three-dimensional crown ethers with n i t r o g e n bridge heads ( 3 - 6 ) . T h i s added dimension r e s u l t s i n an almost s p h e r i c a l i n t r a m o l e c u l a r c a v i t y that i n c r e a s e s t h e i r s t a b i l i t y f o r complexa t i o n with s p h e r i c a l c a t i o n s by s e v e r a l orders of magnitude over p l a n a r crown e t h e r s . Cryptands have been used i n chemical synt h e s i s as l i g a n d s to introduce c a t i o n s i n t o a p r o t i c s o l v e n t s . They are commercially a v a i l a b l e or can be synthesized e a s i l y from i n expensive s t a r t i n g m a t e r i a l s and are r e l a t i v e l y nontoxic. Cryptâtes are i n c l u s i o n complexes formed between c a t i o n s and cryptands. T h e i r b i c y c l i c s t r u c t u r e r e s u l t s i n a f l e x i b l e three dimensional c o n f i g u r a t i o n w i t h a c e n t r a l c a v i t y capable of accepting and complexing c a t i o n s to v a r y i n g degrees. Because the I n t e r n a t i o n a l Union of Pure and A p p l i e d Chemistry (IUPAC) nomenclature f o r these compounds i s cumbersome, they are commonly described by number and i d e n t i t y of donor atoms i n each chain between the bridgehead n i t r o g e n s . In most cases the donor atoms are oxygen i n e t h y l ether l i n k a g e s . As an example, the c r y p t a t e i n Figure 1 i s r e f e r r e d to as Î T Î 2 . 2 . 2 ] because there are two oxygen atoms i n each of three chains.


14.

Cryptate

K R O H N ET AL.

Complexes

201

Cryptâtes are h i g h l y l i p o p h i l i c molecules that r e a d i l y cross b i o l o g i c a l membranes (8) and a r e t h e r e f o r e p o t e n t i a l molecules f o r measuring blood flow. The i n v i v o behavior of cryptâtes would be expected to be dominated by the h i g h l y l i p o p h i l i c surface o f the cryptand surrounding the charged r a d i o i s o t o p e . The b i o l o g i c a l model f o r these t r a c e r s might be that of an i n e r t , f r e e l y d i f f u s i b l e i n d i c a t o r that could be i n t e r p r e t e d by the formalism used f o r i o d o a n t i p y r i n e (9). A l t e r n a t i v e l y , these radiopharmaceuticals might be extracted very r a p i d l y i n d i r e c t p r o p o r t i o n to blood flow, but then the cryptand and t r a c e r might promptly d i s s o c i a t e w i t h i n the c e l l and r e t a i n the i o n a t the l o c a t i o n where i t was i n i t i a l l y d e l i v e r e d . This mechanism would l e a d to the experimenta l methods and data a n a l y s i s used f o r microspheres (10). Cation-cryptand complexes have a wide range o f d i s s o c i a t i o n r a t e s that c o r r e l a t e with the compatability i n s i z e o f the c a t i o n and the crypt and with the charge on the c e n t r a l i o n . Loosely f i t t i n g complexes are weakly bound, independent of charge. Other c a t i o n s are too l a r g e and form e x c l u s i o n complexes. Those o f optimal dimensional matching between c a t i o n and crypt form maximally s t a b l e i n c l u s i o n complexes. A compilation o f l i t e r a t u r e data (11-13) has r e s u l t e d i n Figure 2, a p l o t of d i s s o c i a t i o n constant as a f u n c t i o n of molecular dimensions. For each o f the three cryptands, there i s a minimum i n the f i r s t - o r d e r r a t e constant f o r d i s s o c i a t i o n , representing a maximum s t a b i l i t y . Synthesis

of Cryptate

Complexes

We began t h i s f e a s i b i l i t y p r o j e c t with cryptand [2.2.2] and the monovalent Ag - 110m and d i v a l e n t Sr-85 c a t i o n s . These two metal ions have diameters o f approximately 0.250 and 0.254 nm, r e s p e c t ively (14). The i n t e r n a l diameter o f [2.2.2] has been estimated by CPK s p a c e - f i l l i n g models to be 0.28 nm (3,15). Cryptate complexes form r e a d i l y upon mixing a s o l u t i o n containing the t r a c e r c a t i o n w i t h a s o l u t i o n of cryptand. In order to insure complete complexation we used a molar r a t i o of l i g a n d to i o n o f three. In the complexation r e a c t i o n cryptand must compete with solvent molecules f o r the c a t i o n s i n s o l u t i o n . Thus solvents such as methanol w i t h low d i e l e c t r i c constant and s o l v a t i n g power o f f e r a p r e f e r r a b l e r e a c t i o n environment but we have achieved q u a n t i t a t i v e y i e l d s i n water. The main problem encountered i n syntheses of cryptâtes has been the presence of other c a t i o n s such as Na and competing f o r the cryptand. Care i s taken to minimize the concentration o f competing c a t i o n s o f s i z e s i m i l a r to the c a t i o n intended f o r complexation by using l i t h i u m s a l t s f o r buffering solutions; +

Results with Ag r2.2.2] i n Mice. In the f i r s t s e r i e s o f e x p e r i ments, Ag [2.272] was i n j e c t e d i n t o the t a i l v e i n of r e s t r a i n e d but a l e r t Balb/C mice. Animals were s a c r i f i c e d by d e c a p i t a t i o n +


202

RADIONUCLIDE

GENERATORS

Figure 1. Three-dimensional s t r u c t u r e of cryptand [2.2.2] complex with metal M+. The IUPAC name f o r t h i s l i g a n d i s 4,7,13,16,21,24-hexaoxa-l,10-diazabicyclo-[8.8.8] hexaxosane.

0.6 METAL

ION

0.8

1.0

RADIUS

IN

1.2

1.4

CRYSTALLINE

I.β LATTICE

(A)

Figure 2. The d i s s o c i a t i o n constants f o r cryptâtes depend on the r e l a t i v e s i z e o f the metal i o n and the c a v i t y i n the cryptand.


14.

Cryptate

KROHNETAL.

Complexes

203

at 1, 2, 3, 15 and 60 minutes a f t e r i n j e c t i o n . Selected t i s s u e s were d i s s e c t e d , weighed, counted and reported as percentages of i n j e c t e d dose (% ID) by comparison with a weighed standard of injectate. The r e s u l t i n g d i s t r i b u t i o n data are shown i n F i g u r e 3. The peak concentration i n a l l of the t i s s u e s occurred at 1 to 2 minutes a f t e r i n j e c t i o n and c o r r e l a t e d with blood flow expressed i n terms of a percentage of c a r d i a c output as measured by micro spheres (% CO). This l a t t e r reference data comes from measure ments i n r a t s under halothane anesthesia (10) and should be viewed i n l i g h t of a l l the precautions necessary i n i n t e r p r e t i n g micro sphere measurements as percentages of c a r d i a c output. Figure 4 i s a r e g r e s s i o n p l o t of the c a r d i a c output data versus the maximum % ID/organ f o r seven t i s s u e s . The measurements f o r f i v e organs (muscle, gut, heart, spleen and brain) l i e very c l o s e l y to the l i n e of i d e n t i t y . The value f o r l i v e r may be more accurate f o r Ag+[2.2.2] but depressed i n the microsphere measurements which used anesthetized animals and may i n v o l v e shunting. The measure ment f o r the kidney was probably more accurate by microspheres, whereas, the c r y p t a t e measurement may have been low because t r a c e r d e l i v e r e d to the kidney was l o s t to our measurement because of i t s rapid excretion. The data are a l s o compared (Figure 3) with the 60 min d i s t r i bution of g a l l i u m c i t r a t e and the 24 hr d i s t r i b u t i o n of f i b r i n o gen. These data are taken from the l i t e r a t u r e (16) and represent plasma volume to a f i r s t approximation. The c r y p t a t e d i s t r i b u t i o n showed no apparent c o r r e l a t i o n with the p r o t e i n d i s t r i b u t i o n s , as would have been expected i f the c r y p t a t e had d i s s o c i a t e d i n s t a n taneously, with subsequent tagging of plasma p r o t e i n s . The blood clearance curve of Ag+|_2.2.2] e x h i b i t e d two phases when p l o t t e d s e m i l o g a r i t h m i c a l l y (Figure 5a). The i n i t i a l c l e a r ance (Ί%) of Ag [2.2.2] was 45 sec. The d i s s o c i a t i o n r e a c t i o n , Ag [2.2.2] + Ag" "[2.2.2], i s a f i r s t - o r d e r k i n e t i c process with -3 -1 a r a t e constant of 2 χ 10 sec , which i s the s t a b i l i t y constant f o r Ag [2.2.2] i n aqueous s o l u t i o n at 22°C (13). Our model as sumes that once a s i l v e r c r y p t a t e d i s s o c i a t e s , the r a d i o a c t i v e s i l v e r i o n does not r e t u r n to a cryptand home, but r a t h e r i s bound to plasma p r o t e i n s , which i s a reasonable assumption. Using t h i s model we were able to simulate the blood clearance k i n e t i c s measured i n mice (Figure 5b), i n c l u d i n g the c o r r e c t i n t e r c e p t . The Ag c r y p t a t e experiments have thus i l l u s t r a t e d that the d i s t r i b u t i o n p r o p e r t i e s i n mice peaked immediately a f t e r i n j e c t i o n with % ID/organ values that were approximately equal to l i t e r a ture values f o r % CO to those organs. In a d d i t i o n , these s t u d i e s have shown that the a c t i v i t y i n the b r a i n was constant from 1-3 minutes at 0.75% ID/g, c o n s i s t e n t with rodent c e r e b r a l blood flow (10). This i m p l i e s that A g [ 2 . 2 . 2 ] crosses the blood b r a i n bar rier. A l s o , modeling of the blood clearance curve showed that A g [ 2 . 2 . 2 ] d i s p r o p o r t i o n a t e d i n plasma with a r a t e constant equal to that which would be expected from the k^ f o r Ag+[2.2.2] i n +

+

H

+

+

+


RADIONUCLIDE

204

J

I

I

I

I

I

2

3

15

60

I %C.O.

I Go(60min)

GENERATORS

I Fib(24h)

A g+[2.2.2] +

F i g u r e 3. T i s s u e d i s t r i b u t i o n o f A g [ 2 . 2 . 2 ] i n v a r i o u s t i s s u e s o f mice. Comparison d a t a i s g i v e n f o r percentage o f c a r d i a c o u t p u t going t o each t i s s u e and f o r the d i s t r i b u t i o n o f two common p r o t e i n m a r k e r s .


KROHN ETAL.

Ο

Cryptate

Complexes

ι

r

10

20 %

205

30

40

ID/ORGAN

F i g u r e 4. The p e r c e n t a g e o f Ag+[2.2.2] i n s e v e r a l o r g a n s s h o r t l y a f t e r i n j e c t i o n c o r r e l a t e s w e l l with the percentage o f c a r d i a c o u t p u t . The l i n e o f i d e n t i t y i s i n c l u d e d f o r reference.



206

•5h

* 0

15

30

TIME

45

60

(min) +

F i g u r e 5a. The b l o o d c l e a r a n c e o f A g [ 2 . 2 . 2 ] was b i p h a s i c , s u g g e s t i v e o f decomposition of the c r y p t a t e i n v i v o .


K R O H N ET AL.

Cryptate

Complexes

207

100

TIME (min) F i g u r e 5b. The c l e a r a n c e c u r v e c a n be s i m u l a t e d u s i n g a model o f A g [ 2 . 2 . 2 ] -> 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



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 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


14.

Cryptate

KROHNETAL.

"i

Complexes

209

Γ

+ +

Sr C2.2.2]

Ψ

Ο à

Ν

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•

•

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f

•\

Δ

V

\

Ξ

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Lung · Spfotn * J

I

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I IONIC Sr C l

15

TIME

Figure

6.

tissues chloride

Tissue

of mice. a t 15

Livtr Δ Out Ο Heart •

• I

2

,

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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.


the

210

RADIONUCLIDE

GENERATORS

+ +

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.


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. + +

+

+

+ +

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-

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212

RADIONUCLIDE

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Cryptate Complexes of Generator-Produced Isotopes - ACS

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