CA1198549A - Stabilization of radiolabeled organic compound - Google Patents

Abstract

ABSTRACT

A compound for stabilizing a solution of a radiolabeled organic compound that is subject to radiolytic degradation against such degradation comprises a substantially insoluble substrate having pendant quaternary ammonium and optionally sulfide groups; the solution of the radiolabeled organic compound is maintained in contact with the compound having pendant quaternary ammonium groups, thereby stabilizing the radiolabeled organic compound against such degradation.

Description

This invention relates to the stabilization of radiolabeled compounds, such as amino acids and nucleosides, and more par~icularly, to stabilization of such compounds by the addition of soluble and insoluble compounds to solutions of radiolabeled compounds.
This application is a division of Canadian Patent Application Serial No. 356,336, filed December 8, 1930.
An increasing number of radiolabeled compounds are being used in research, for medical diagnosis, and various other areas.
However, the radiolytic decomposition of such compounds has been a con-stant problem. ~ithout the addition of some type of stabilizer7 a solution of such a compound may become unusable due to decomposition within a matter of weeks or less. This radiolytic clecomposition of such compounds has been studied extensively. For example, the radiation chemistry of amino acids is reviewed in an article by J.
Liebster and J. Kopeldova, Radiation Biol., 1, 157 (1~64) and the self-decomposition of radioactively labeled compounds is discussed in Atomic Energy Review, 10, 3-66 ~1972). While certain specific compounds have been suggested for stabilization, problems still exist. The latter article reviews the underlying causes and mechanisms of self-decompo-sition, "which are very complex and in some cases not well understood."
(At p. 3). After discussing the principal mechanisms by which decom-position occurs, the article notes generally at page 36 that buffers such as ammonium bicarbonate help to stabilize radiolabeled compounds, but care must be taken to insure that the buffer chosen does not interfere with the later use of the labeled compound. For example, phosphate buffers would interfere with phosphorylation reactions.
Other compounds which have been suggested at various times are listed at page 35 and include benzyl alcohol glycerol, cysteamine and sodium formaten However, each of these are said to suffer due to their difficulty of removalO
Another compound mentioned is ethanol which is said to work with many compounds. However, ethanol sometimes actually sensitizes certain nucleosides to radiation decomposition and thus it has been found not to be a universal panacea~
Furthermore, if it will interfere with the reaction in which the radiolabeled compound lS to be u.sed, the ethanol must be removed by evaporation which may also contribute to decomposition.
Various compounds are sugges~ed in Atomic Enerqy Review, above, for stabiliæation of radiolabeled compounds prone to oxidation including antioxidants such as butylated~
hydroxytoluene, butylated-hydroxyanisole and mercaptoethanol.
While not mentioned for use with radiolabeled compounds, the inhibition of autoxidation generally by certain amines has also been described in the prior art. Recent reviews on the inhibition of autoxidation are "Autoxidation" by R. Stroh, p~ 1049 in Methoden der Or~nischen Chemie (Houben-Weyl), ed. E. Muller and O. Bayer Vol. IV/Ib Oxidation Il~, Georgthieme Verlag, 1975, and Encyclopedia o-f Chemical Technolo~y, Kirk Othmer, Interscience Publishers, New York.
The prior art teaches the utility of secondary dialkyl amines bearing full alpha-substitution (i.e~, containing no hydrogens on the carbon atoms adjacent to the nitrogen) and secondary diarylamines (also without alpha-hydrogens) as antioxidants. However, the prior art does not teach the use of primary, secondary and tertiary amines, those containing alpha-hydrcgens, in this regard and in fact suggests that they are not effective for this purpose~ However, such anti~
oxidants have many of the same problems as other of the 5 ~

~ompounds discussed above, including in addition generally being insoluble in the solvents used to di~solve and store radiolabeled compounds for use in biolo~ical studies Accordingly, th~ra has been a continuing need for alternati~es to the stabilizers known in the prior art The synthesis and use of polystyr~ne supported reayents for solid phase peptide preparation i~ k~own in the t prior art. R. B. Merrifield, J. Am, Chem. Soc., 85, 2149 s (1963~; Crowley et al, Ac~t~. Ch,_m. Res., 9, 135 (1976), G. Ro Stark (1971), Biochemical Aspects of Reactions on 501id Supports, Academic Press, ~.Y., U.S. Patents ~,9~8,293 and 4,029,706 describe thio~ydrocarbon polymers and their use a~ borane chelators, However, neither the synthesis nor use of the insoluble compounds of the present invention ~re described in anly o thP above.
In accordance with the invention there is proYided a ~; '' .
compound for stabilizing a solution of a radiolabeled organic compound that is subject to radiolytic degradation against said degradation comprising a substantially insoluble resinous substrate having pendant quaternary ammonium and sulfide groups.
In another aspect of the invention there is provided a method of making the compounds of the invention which com-prises reacting an alkyl thiol and a trialkylamine with a sub-stantially insoluble resinous substrate having a reactive site.
In still another aspect of the invention there is provided a composition comprising a solution of a radiolabeled organic compound that is subject to radlolytic degradation, said solution being maintained in contact with a compound hav-ing a quaternary ammonium group bound to a substantially in-soluble substrate, thereby stabilizing said radiolabeled organic compound against said degradation.

35~

There is disclosed herein a meth~d of stabilizing a ~olution of a radiolabeled compound comprising adding to such solution a compound having a substantially insoluble backbone, preferably a resin, such asan ion exchange resin9 to which has been bound a quaternary ammonium group; or a water soluble primary, secondary or tertiary aliphatic amine which does not interfere with ~he use contemplated for the particular radio-labeled compound so stabilized. There is also disclosed a solution of a radiolabeled compound maintained in contact with such compound7 and as an artîcle of manufacture, a sealed vial. containing such a solution~
It has been found that various amines and quaternary ammonium compounds stabilize solutions of radiolabeled compounds. A pri.or application, describes the stabilization of radiolabeled i~,7 ~ 3 ~1 --s~

compounds by maintaining a solution of such a labeled com-pound in contact with a compound having a quaternary a~nonium group bound to a substantially insoluble backbone Even before the earlier application was filed the present inventors had discovered that certain soluble amines would act as stabilizers of radiolabeled compound~. That earlier application describes one specie.
While originally believed to not only stabilize solutions of radiolabeled compounds, but to do so without adulterating such solutions, further studies using both soluble am1nes and insoluble quaternary ammonium containing compounds have shown that such quaternary ammonium containing compounds stabilize such solutions at least in part by the release of soluble amines. For example, the polystyrene-divinyl benzene copolymer substituted by triethyl ammonium as described in Example VII below provides stabilization, at least in part, by the release of soluble triethyl amine, a tertiary aliphatic amine. At the same time, it has also been found that depending on how the radiolabeled compound is to be used, the presence of such soluble amines is compatible with the ultimate use for th~ labeled compound. While care must be exercised to insure that the particular stabilizer does not interfere with the ultimate use for the radiolabeled compound, it has been found that soluble amines are generally useful for stabilizing 301utions of such radiolabeled com-pounds in the 9ame manner as amines which are released into ~olution from insoluble sub~trates to which they have pre-viou~ly been bound. For the 3ake of convenlence, the species ~ill be described separately for the most part, although it should be recognized that all the species stabilize, at least in part, by virtue of their presence in solution.

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~ he substantially insoluble quaternary ammonium containing compounds disclosed herei~ can be any o~
those well known in the prior art. A preferred class of such compounds is that prepared by attaching quaternary ammonium groups to an insoluble polystyrene-divinylbenzene copolymer backbonel e.g., a copolymer formed by copolymerizing about 1% to about l~/o by weight of divinylbenzene with styreneO The preparation of such copolymers i5 well known in the prior art and they are sold commercially for use as anion exchange resins. Such commercially available copolymers are ! preferably treated by washing with ethanol and then methylene chloride, followed by drying before being employed to stabilize radiolabeled compounds~
The nitrogen of the quaternary ammonium group is preferably substituted by hydroxyalkyl or alkyl chains, preferably lower alkyl, and more preferably of from 1 to 5 carbon atoms.
The counterion (anion) of both the soluble and in-soluble quaternary compounds of the present invention can be any of those known in the prior art which do not significantly detract from the stabilization provided by the quaternary ~mmon;um group, Preferred counterions are halides and alkyl carboxylate ions of one to five carbon atoms, such as formate and acetate. A particularly preferred counterion is chloride.
Particularly preerred for use in the present invention æ e novel compounds prepared by attaching a sulfide or thiol group to the substantially insoluble stabilizing compounds described above. Preferred sulfide groups are those substituted by an alkyl group of one to five carbon atoms.

Insoluble ammonium sulfide compounds have been found to be particularly effective in stabilizing solutions of radio-labeled compounds.

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With respect to amines and quaternary ammoniumcompounds soluble in the aqueous solutions usecl to store radiolabeled compounds for biological use, it has been found -that such compounds may be ~elected fxom the group consisting of.
a) RNH2' b) RR NH, c) RRlR ~, d) R3R N-R-~R3R4, and e) R3~4N - I Rl-NR R

NR R n and quaternized salts thereof, wherein R, Rl and R2 are the same or different and are alkyl, cycloalkyl, alkenyl, hydroxyalkyl, aminoalkyl, thioalkyl, carboxyalkyl, or keto alkyl of one to eight carbon atoms, or R and of RRl~H are combined to form a chain ~f foux to 5iX
carbon atoms at ached at each end to N, or one of the carbon atoms of the chain may be replaced by 0 or N, R3 and R are the same or different and are hydrogen or R, R or R ; and n is an integer between 0 and 1000.
Preferred soluble amines include triethylamine, tris (hydroxymethyl) methyl amine, hydroxyethylpiperazine ethyl sulfate, morpholine ethyl sulfate, and quaternary salts derived therefrom, p~rticularly preferred such salts being triethylamine hydrochloride and tris (hydroxymethyl) methyl ammonium hydrochloride.
While any amount of the st~bilizer compounds described above is beneficial in preventing the decomposition of radiolabeled compounds, in the case of the quaternary ~ 6 --s'~

ammonium subst~ntially insoluble stabilizers it is preferred that the nitrogen be in excess equivalents of between about and about 10 , more pre~erably between about 10 and 10, and most preferably about 10 . When a sulfide or thiol group is attached to the backbone, it is preferred that the sulfur be present in equivalent excesses between about 10 and 105, preferably between about 103 and about 104, and most pre-ferably about 104. By equivalent excess is meant, an excess of the respective atom, e.g., nitrogen, in the stabilizing compound over the equivalents of the radiolabeled compound. Similarly in the case of soluble compounds, it is preferred that the stabilizing compound be present at con-centrations between about 1 millimolar through about one molar depending on the specific activity of the radio-labeled compound, the concentration of khe radiolabeled compound in the solution, and the particular radioisotope being employed as the label. In general, it is preferred that the concentration of stabilizing agent be 103 to 10 times the concentration of labeled compound. For example, a tritiated compound with a specific activity of 100 Ci/rnMole would preferably contain between about 10 and about 20 mM
concentration of amine; a 10 excess. Sirnilarly, if the label u~ed is phosphorus-32 which might produce a specific activity of 1000 Ci/r~Mole, a one molar ~oncentration of ar~ne would be preferred, a 105 excess.
In addition to the use of any of the above described amines alone, in some instances, it is preferred to use the soluble amines in combination. Pre~erred cornbinations are tris ~hydroxymethyl) methyl arnmonium hydrochloride and either ethylenediamine-tetraacetic acid (EDTA~ or diethylenetriamine-pentaacetic acid (~ETAPAC). Such combinations are parti-35(~93 cularly preferred for stabilizing the storage of nucleotides and preferably employed in a ratio of about 10:1 of the former to the latter with the overall ratio of labeled com~
pound to stabilized compound being as above. EDTA and DETAPAC are also known to function as chelators of metal ions and thus cannot he used when the stabilized cornpound is to later be used in a reaction where chelation of metal ions must be avoided.
The method disclosed herein can be used with any o~ the solvents typically used to store radio-labeled compounds such as water, ethanol, mixtures of water and ethanol in any ratio, benzene, hexane, dilute mineral and organic acids, and other such solvents employed in the prior art~
The present invention can be used to prevent the decomposition of radiolabeled compounds which have been labeled with any of the radionuclides used for such purposes, including tritium, carbon-14, phosphorus-32, phosphorus-33, sulfur-35 and the various radioisotopes of iodine, including iodine-125 and iodine-131.
The radiolabeled compound may be any of those subject to radiolytic decomposition, such as radiolabeled organic compoundq. Examples o-~ such organic cornpounds include amino acids such as lycine, tyrosine, phenylalanine and tryptophan.
; rThe stabilizing compounds are particularly effective with methionine and leucine. Other swch organic compounds include peptides; nucleoside.s, such as thymidine and uridine, nucleotides, polynucleotides, lipidsl steroids and catecholamines.

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Radiolabeled compound~ are typically commercially distributed in closed vials containing a solution of the particular radiolabeled compound. Stabilizing compounds with an insoluble backbone can take various forms as long as they are maintained in contact with the solution of radiolabeled compound. An example of a possible form is solid beads which are added to a solution of the radio-labeled compound, in which case the solution would be removed from the stabilizing compound by decanting sr withdrawing by means of a syringe, Another potential means of storage would be to pro~ide the stabilizing compound in a form whereby the solution of the radiolabeled compound would be absorbed by the stabiliæing compound.- In such a case, the solution of radiolabeled compound would be eluted from the mass of stabilzing compound by use of a suitable solvent. Once separated, the solution of radiolabeled compound is used in the same manner as unstabilized solutions thereof. In the case of soluble amine~, the sta~ilizing com~ound is simply added to a solution of the radiolabeled compound which is typically shipped in a sealed vial from which the stabilized compound is removed by withdrawing by means of a syringe.
The invention will be further clarified by a con-sideration of the following examples, which are intended to be purely exempl~ry of the use of the invention.
EXAMPLE I
Preparation of Polystyrene-divinylbenzene bound ammonium ~ulfide, chloride form To a suspen~ion oE chloromethylated polystyrene copolymerized with ]% divinylbenzene (10 g, 42 5 milli-equivalents chloride by analysis) in methylene chloride (200 ml) was added ethanethîol (15~7 ml, 213 mMol) and triethylamine (29.6 ml, 213 mMol). A slight yellow color began to develop after approximately 10 minutes and the mixture was allowed to stir -for 60 hrs. under a nitrogen atmosphere. The resultant suspension was filtered through paper and continuously extracted with chloroform for 24 hrs., ethanol 3 hrs~, then washed with chloroform (5 x 40 ml), ethanol (5 x 40 ml) and the white resin that remained was dried in a vacuum oven at 60C/20 mm to leave 10 g of the ammonium sulfide polymer. The analysis of C, 71.18, H, 8.84; N, 215, S, 4.90, Cl, 5.26 indicates 1.53 mequivalents - Sulfur/g, 1.53 mequivalents ~itrogen/g, and 1.48 mequivalents Chloride/g of polymer resin.
EXAMPLE II
Preparation of the Ammonium Sulfide Polymer in its acetate form The ammonium chloride of Example I (3g) was stirred with 1~ NaOH (100 ml) for 3 hours, filtered and washed three times successively with methylene chloride (50 ml) then ethanol (50 ml). The resultant resin was dried ovexnight at 23C/20 mM to afford 2~7 g of a yellow product which analysed for C, 73.39; H, 8~83; N, 1.90, S, 4.78 Cl, 3008. This analysis indicates 1~36 mequivalents j Nitrogen/g, 1.49 mequivalents Sulfur/g, and 0.88 mequivalents Chlcride/g of polymer resin~
The yellow product above was washed with l~/o aqueous acetic acid (100 ml) then three times successively , with methylene chloride (40 ml) followed by ethanol (40 ml).
The resultant white product was dried at 23/20 mM to afford Example II as the acetate 2.7 g, The following Examples demonstrate the use of various insoluble quaternaxy ammonium containing compounds and soluble amines to stabilize various radiolabeled compounds~ The -- 10 -.

analytical method employs liquid ch.romatography for separation followed by post column radioactivity quantitization. The values given are an average of three separate determinations from triplicate packagings.
EXAMPLES III - V
The following examples detail the storage of tritium-labeled methionine in aqueous ethanol solution with an initial radiochemical purity of 9~/O with the stabilizers of E~Yamples I and II. The average change in purity is based upon three ind1vidual determinations~

Average Number ofChange in Molar ' Ex~ Stabilizer Days StoredPurity (%) Excess ;
None 47 6 : 118 19 III Compound 47 1 3 of Ex. I 62 3 1.2 x 10 87 4 of Sulfur ` 118 11 and Nitrogen j . IV Compound 48 O 8.7 x 10 of Ex, I 62 O of Sulfur 87 O and Nitrogen V Compound 47 2 1.2 x 10 of Ex. II 62 4 of Sulfur 87 5 and Nitroger An aqueous solution of methionine having an initial purity of 93% was divided into equal parts, One part was stored without any sta~ilizer, while the other part was stored over 4~5 x 10 molar excess of the compound of Example I.
Ater 36 days the change i.n radiochemical purity was 75% and 12% respectively~ After 66 days the change in radiochemical purity was 85% and 19% respectively, and the biological activity of the two solutions was tested by attempting to use the stored solutions for protein translation~ The solution of methionine stored without any stabilizer failed to translate effectively, whereas the solution stored over stabilizer underwent efficient protein translation.

Average Number of Change in Molar E Stabilizer Days Stored Purity (%) Excess None 36 75 VI Compound 36 12 4.5 x 10 of Ex. 166 19 of Sulfur and Nitrogen EXAMPLES VII and VIII
Examples VII and VIII illustrate the use o-f the present invention with the stabilizer of Example I and poly-styrenedivinyl benzene copolymer substituted hy triethyl a-mmonium wi~h chloride as the counterion (TEAC) to stabilize a solution of tritium labeled lysine with a starting purity 20 of g8.5%.

Average Nur~er of Change in Molar Ex~ Stabilizer Days Stored Purity (%) Exce~s _ None 34 300 6.0 VII TEAC 34 0.5 105 x 10 1.5 of Sulfur and Nitrogen VIII Compound 34 0~5 3 of Ex. 1 70 1.5 1.5 ~ 10 o-f Sulfur and Nitrogen EXAMPLES IX-XII
Example~ IX - XII illustrate the use of the present invention to stabilize a radiolabeled nucleoside, tritium-labeled thymidine. Example~ IX and X employ th~ stabilizer of Example I, whereas Examples XI and XII employ a commercially available polystyrenedivinyl benzene copolymer anion e~change r~sin to which has been bound a trimethyl ammonium group with chloride as the counterion (TMAC) in accordance with the present invention.

Average Number of Change in Molar Ex, Stabilizer Days Stored Purity (%) Excess None 14 3 IX Compound14 0 10 Nitrogen of Ex. 1 22 5 and Sulfur X Compound 14 0 2 x 104 of Ex. 1 22 2 Nitrogen 29 2 and Sulfur XI TMAC 14 0 10 Nitrogen XII TMAC 14 0 2 x 10 22 3 Nitrogen 2g EXAMPLES XIII - XV
The following examples detai.l the storage of tritium labeled methionine (80 Ci/m~ol) in aqueous 7~/O
ethanol solution with an initial radiochemical purity of 98% to give 1 mCi/ml at -20C with amines as indicated~
EXAMPLE XIII

. Average Number of Change in StabilizerDays Stored Purity ~%) Molarity ~one 79 12 Cyclohexyl isopropyl amine 79 5 20 mM

EXAMPLE XIV

Average Nur~er of Change in 5tabilizer Days Stored Purity (%) Molarity None 45 6 1,5-Diaminopentane 50 1 20 mMolar 1,6-Diaminohexane51 1 20 mMolar . 114 EXAMPLE XV

Average Number of Change in Stabilizer Days StoredPurity (%) Molarity ~one 45 6 triethyl amine 49 1 0.7 mM

EXAMPLE XVI
The following example details the storage of tritium labeled methionine (80 Ci/mMol) in water with an initial radiochemi.cal purity of 94% to give a concentration of 1 mCi/ml at 4C with the amine as indicated~

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EXAMPLE XVI

Average Number of Change in StabilizerDays Stored Purity (%) Molarity None 6 21 22 ~

Triethylamine 6 3 lOmMolar ~3 EXAMPLES XVII - XVIII
The following examples detail the storage of sulfur-35 labeled methionine (1000 Ci/mMol) in water with an initial radiochemical purity of 95% to give a concentration of 10 mCi/ml with the amines as indicated. Examples XVII and XVIII were stored at 4C while Example XIX was stored at -20C. Tr.is refers to tris (hydroxymethyl) methyl amine.
EXAMPLE XVII

Average Number of Change in StabilizerDays Stored Purity ~%) Molarity None 1 17 triethyl amine 2 14 1 Molar ~ 1 triethyl amine 2 15 lOOmMolar EXAMPLE XVIII

Average Number of Change in Stabilizer Days Stored Purity (%)Molarity None 1 8

2 15 18 ~36 Tris*(as free ~ase) 1 4 1 Molar ~ 18 35 EXAMPLE XIX

Average ~umber of Change in Stabilizer Days Stored Purity (%)Molarity None 3 6 Tris.HCl 3 0 lOmMolar EXAMPLE XX
Example XX details the storage of tritium labeled Enk~phalin ~5-L-methionine) (30 Ci/mMol) in an aqueous solution containing 70/O ethanol with an initial radio-chemical purity of 98% to give a concentration of 1 mCi./ml at -20 with various amines as indicated.

Average Nu~ber of Change in Stabilizer Days Stored Purity (%)Molarity None 26 13 Triethylamine 26 0 33 mMolar Hepes 26 4 3 mMolar (hydroxyethyl piperazine ethyl sulfate) * Tris(hydroxymethyl)methyl amine EXAMPLE XXI
Example XXI details the storage of tritium labeled chemotactic peptide (57 Ci/mMol) in an aqueous solution con-taining 50/O ethanol with an initial radiochemical purity of 99/O to ~ive a contentration of 1 mCi/ml at -20C with polylysine.hydrobromide (av. M.W~ 20,000).

Average Number of Change in StabilizerDays Stored Purity (%) Molarity None 54 4 Polylysine.HBr54 1 1 mMolar EXAMPLES XXII - XXIII
Examples XXII and XXIII detail the storage of deoxyguanosine-5'~triphosphate labeled with phosphate-32 (660 Ci/mMol) in water with an initial radiochemical purity of 95% to give a concentration of 10 mCi/ml at -30C with the amines indicated. EDTA is an abbreviation for ethylene diamine tetracetic acid.

EXAMPLE XXII

Average Number of Change in StabilizerDays Stored Purity (%) Molarity None 9 9 Tris (free base) 9 5 800 mMolar Tris.HCl 9 5 800 mMolar Triethylamine 2 3 800 mMolar EXAMPLE XXIII

Average Number of Change in 5tabilizer Days Stored Purity (%)Molarity None 10 14 Tris.HC1 10 750 mMolar Tris.HCl 10 810 mMolar EDTA 10 71 mMolar Tris.~Cl/EDTA 10 310mM/lmM

Example XXIV details the storage of labeled Adenosine-5~-triphosphate labeled with phosphorus-32 (8100 Ci/m~lol) in water at an initial radiochemical purity of 97%
to give a concentration of 3 mCi/rnl at -30C with triethyl-amine, Average Number of Change in Stabilizer Days Stored Purity (%) Molarity None 13 7 Triethylamine 17 6 4 mMolar Triethylamine 17 3 40 mMolar Triethylamine 13 0 400 mMolar Other embodiments of the invention will be apparentto those skilled in the art from a consideration of this specification or practice of the invention disclosed herein.
It is intended that the specification and e~amples be con-sidered as exemplary only, with the true scope and spirit of the invention being indicated by the -followlng claims.

Claims (19)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A compound for stabilizing a solution of a radiolabeled organic compound that is subject to radiolytic degradation against said degradation comprising a substantially insoluble resinous substrate having pendant quaternary ammonium and sulfide groups.

2. A compound as claimed in claim 1, wherein said substantially insoluble resinous substrate is a polystyrene-divinyl benzene copolymer.

3. A compound as claimed in claim 1, wherein said quaternary ammonium group is substituted by lower alkyl.

4. A compound as claimed in claim 3, wherein said alkyl group contains from one to five carbon atoms.

5. A compound as claimed in claim 1, wherein the counter ion of said quaternary ammonium group is a halide or a lower alkyl car-boxylate anion.

6. A compound as claimed in claim 5, wherein said counter ion is chloride.

7. A compound as claimed in claim 1, wherein said sulfide group is substituted by lower alkyl.

8. Polystyrene-divinylbenzene ammonium chloride lower alkyl sulfide.

9. Polystyrene-divinylbenzene ammonium acetate lower alkyl sulfide.

10. A method of making a compound as claimed in claim 1, comprising reacting an alkyl thiol and a trialkyl-amine with a substantially insoluble resinous substrate having a reactive site.

11. A composition comprising a solution of a radio-labeled organic compound that is subject to radiolytic degra-dation, said solution being maintained in contact with a com-pound having a quaternary ammonium group bound to a substanti-ally insoluble substrate, thereby stabilizing said radiolabeled organic compound against said degradation.

12. A composition as claimed in claim 11, wherein said radiolabeled compound is a radiolabeled amino acid.

13. A composition as claimed in claim 11, wherein the quaternary ammonium group bound to a substantially insoluble substrate is substituted by lower alkyl.

14. A composition as claimed in claim 11, wherein said compound having a quaternary ammonium group bound to a substantially insoluble substrate is a quaternary ammonium substituted polystyrene-divinyl benzene copolymer.

15. A composition as claimed in claim 11, wherein the counterion of said compound having a quaternary ammonium group bound to a substantially insoluble substrate is halide or a lower alkyl carboxylate anion.

16. A composition as claimed in claim 11, wherein said compound having a quaternary ammonium group bound to a substantially insoluble substrate, in addition, contains a sulfide group.

17. A composition as claimed in claim 16, wherein said compound having a quaternary ammonium group bound to a substantially insoluble substrate and a sulfide group is a polystyrene divinyl benzene ammonium sulfide.

18. A composition as claimed in claim 11, wherein the solvent of said solution is water, ethanol, a mixture of water and ethanol, benzene, hexane, a dilute mineral acid or a dilute organic acid.

19. A composition as claimed in claim 11, wherein the radio-nuclide of said radiolabeled compound is tritium, carbon-14, phosphorus-32, phosphorus-33, sulfur-35, iodine-125 or iodine-131.