GB2087633A - Isotope separation - Google Patents

Abstract

In the separation of short-lived isotopes for medical usage, a solution containing <195 m> Hg is contacted with vicinal dithiol cellulose which absorbs and retains the <195 m> Hg. <195 m> Au is eluted from the vicinal dithiol cellulose by using a suitable elutant. The <195 m> Au arises from the radioactive decay of the <195 m> Hg. The preferred elutant is a solution containing CN<-> ion.

Description

SPECIFICATION Isotope separation This invention relates to the separation of t95mAu from Hg for use in a medical isotope generator.

Short-lived isotopes are required for gamma-scan studies of heart action for at least two reasons, firstly, to permit increased radiation intensity whilst limiting the total radiation dose to the patient, and secondly, to enable repeated photographs to be taken under varying conditions in the same session.

Hitherto.99mTc has been used but it has a half-life of 6 hours and is not entirely suitable. A study of the decay and radiation characteristics of various isotopes has suggested that 195may which has a half-life of 30.5 seconds and is obtained by the decay of '95mHg (half-life 40.5 hours) would be suitable. Thus, l95mAu decays predominantly by emission of a 262-keV gamma ray which is ideal for detector systems presently used in gamma-scan studies. Reference should be made in the above respect to a paper by Lebowitz and Richards, Seminars in Nuclear Medicine, Vol. 4, No. 3 (July), 1974 pages 257 et seq entitled "Radionuclide Generator Systems" and to a paper by Y. Yano in Radiopharmaceuticals, Ed.

Subramanian et al., Soc. Nuc. Med. Inc. N.Y. 1 975, pages 236-245 entitled "Radionuclide Generators: Current and Future Applications in Nuclear Medicine".

195Hg may readily be prepared by carrying out a p,3n reaction on l97mAu using a variable energy cyclotron. It is, however, essential to be able to effect a rapid separation of the 195mAu resulting from decay of the 195mHg and in a form suitable for injection into the bloodstream. The present invention is concerned with the rapid separation of '95mAu from '95mHg.

The invention provides, in a first aspect, a method of separating '95mAu from '95mHg in a solution containing ions of 195mug, wherein '95mAu is generated by radioactive decay of the 195mHg, which method comprises: (i) contacting the solution with vicinal dithiol cellulose thereby to adsorb the 195mHg as Hg++ ions from the solution onto the vicinal dithiol cellulose; and (ii) eluting from the vicinal dithiol cellulose, l95mAu arising from radioactive decay of the l95mHg, by means of an eluting solution containing an eluting agent therefor.

It has been found that the present invention enables l95mAu to be separated effectively and sufficiently rapidly for the resulting '95mAu to be used in the above-mentioned gamma-scan studies.

Thus. the invention may be utilised in an isotope generator, for example where the vicinal dithiol cellulose, which has been contacted with a solution as in step (i), is provided in a separating column and the column eluted as in step (ii). Such an isotope generator constitutes a second aspect of the invention.

Vicinal dithiol cellulose has the general formula R-O-CH2-CHSH-CH2SH where R represents a cellulose polymer, and is known in the art to be effective in removing Hg from solution. See Environmental Science and Technology 8 (1 971), 993. Control of the pH of the solution is an important factor in achieving satisfactory adsorption of Hg in step (i). Thus, it was found that no apparent adsorption of Hg took place when the solution had a low pH. Generally, it is preferred to operate at solution pH's in the range of 1 to 9.

The most satisfactory eluting agent so far identified for use in step (ii) is CN-. Thus, a solution of KCN has been found to be very effective in eluting Au in step (ii) and also has the surprising advantage of appearing to bind the Hg tightly to the vicinal dithiol cellulose. The use of CN- as an eluting agent does, of course, raise the question of what concentration of CN- in the final product is acceptable in terms of tolerance by the patient of ingested CN-. The answer is not known at present but it is believed that the amount of CN ingested by way of the product of this invention could be made very small by carrying out the invention using a small column, the minimum possible concentration of solution and of volume of eluting solution, e.g. 0.25 mg of KCN per 0.5 ml of eluting solution.Alternatively, it might be possible to solve this problem by rendering the CN harmless by complexing with a complexing agent such as Fe++ or Fe+++.

Eluting agents other than CN- may be used in step (ii). Thus, agents with a > C=S group or its equivalent, such as thiourea have appeared to be effective though none so effective as CN-.

The starting solution used in step (i) may be prepared by firstly subjecting a gold foil target to treatment using a variable energy cyclotron when a p,3n reaction takes place to give 195mHg and secondly, separating the Hg from the target by methods known in the art. A specific example of such a separation is provided hereinafter.

The invention will now be particularly described, by way of example only, as follows:- EXAMPLE SEPARATION OF l95mHg FROM AN Au TARGET A gold foil target (--0.5 g) which had been subjected to a p,3n reaction in a variable energy cyclotron was placed in concentrated HCI (5 ml) together with a Hg carrier (1 ml) in a flask. HNO3 (1-2 ml) was added with heating to dissolve the Au. After dissolution was complete, the solution was boiled until brown fumes of NO2 were no longer apparent. A small amount (1-2 ml) of concentrated HCI may be added to speed this process.

The above solution was transferred to a 100 ml cylindrical separatory funnel, and the flask washed with portions of concentrated HCI to give a final volume which was double the original volume and a solution of about 9M in HCI.

An equal volume of amyl acetate was added and the Au extracted by means of vigorous stirring for a few minutes. The phases were separated, the funnel washed with a little amyl acetate, and the aqueous phase transferred back to the funnel, the flask being washed with fresh amyl acetate. This step was repeated three more times.

Finally, the aqueous phase was scrubbed with an equal volume of hexane to remove traces of amyi acetate from the solution. The aqueous solution was boiled for a few minutes to remove traces of hexane to give a final solution of approximately 6M HCI.

PREPARATION OF VICINAL DITHIOL CELLULOSE Alkaline cellulose, prepared as described by Peterson and Sober in a note from Wayne N.

Marchant in Environmental Science and Technology 8, 993 (1974), was maintained at 0--50C during dropwise addition of allyl bromide (1-1.3 ml/g of cellulose). Continuous mixing was provided during this addition by use of a heavy glass rod. The doughy mixture was then transferred to a water bath and maintained at 60-650C for 1-2 hours, with frequent remixing. The product was then suspended in a large volume of water and allowed to settle.

After decanting the supernatant, the process of suspending and settling was repeated until the supernatant was nearly neutral. The material was collected on a suction funnel, washed with ethanol and ether, and air-dried. The etherified cellulose was brominated in a CCI4 slurry using 0.5 g of bromine and 1 5-20 ml of CCI4 per g of solid and stirring overnight. The brominated derivative was added to a methanolic solution of NaSH prepared by dissolving solid sodium hydroxide in methanol and saturating the resulting solution with hydrogen sulphide. After stirring in this medium overnight, the final product was collected on a suction funnel and washed with 5% HCI and then with water until the wash was neutral. After washing with ethanol followed by ether, the material was air-dired.The product was a white, nearly odourless free-flowing powder (vicinal dithiol cellulose).

SEPARATION OF 195mAu FROM 195mug The general procedure was as follows. Vicinal dithiol cellulose, prepared as above, was contacted with a '95mHg solution prepared as above with the modified pH. The resulting material was loaded into a polythene column, which was then washed with water. The radioactivity was measured by means of a Nal single-channel y-ray spectrometer set to accept puises in the 262-keV range. The y-rays detected arise almost exclusively from decay of l95mAu; the total l95mAu activity in equilibrium with the 195mug may therefore be measured directly from the column.

An elution solution comprising aqueous KCN was added and the '95mAu activity in the eluant counted. After the l95mAu activity had decayed completeiy, the eluant was re-counted to measure 195mug activity.

The general procedure was carried out under a variety of process conditions. The results for preparation of the cqlumns are given in Table I below and the results for elution of the columns given in Table II. Vicinal dithiol cellulose is referred to as VDTC in the tables.

TABLE I Mass Hg Activity VDTC % Hg Adsorbing Time for Adsorbed Experiment (mg) Saturation Solution Adsorption (min) % Adsorbed (c/m x 10e) 1 100 2.5 0.01MHCl 15 97 6 2 120 23 20% HOAc 1 Om 99 12 3 13 211 20% HOAc 180 92 4 10 25 50% HOAc 130 96 4.0 5 64 23 H20 15 100 0.5 6 53 9 1% HOAc OVERNIGHT 99 6.5 (Volume increased to 30 ml with H2O) 7 20 100 10% HOAc OVERNIGHT 60% 15 (Volume increased to30mlwithH2O) TABLE II VDTC Elution Mass Concentration of Volume % Au % Hg Au/Hg Experiment (mg) KCN (M) (ml) Eluted Eluted Ratio 8 120 0.01 2 44 0.03 1460 9 100 0.01 2 44 0.05 880 10 13 0.01 2 92 2.8 33 1.5 79 0.03 2630 1.0 33 0.02 1650 0.5 47 0.02 2350 0.25 50 0.01 5000 11 13 0.008 2 45 .07 640 0.006 45 .03 1500 0.004 48 .06 800 0.002 38 0.04 950 12 100 0.008 2 75 0.05 1500 0.006 88 0.02 4400 0.004 80 0.004 20000 0.002 67 0.08 840 13 50 0.006 1 31 0.05 620 0.02 38 0.045 1900 0.05 60 0.06 1200 0 10 62 0.06 620 The results clearly show the ability of the method of the present invention to separate 195mAu from 195mHg As an alternative to the vicinal dithiol cellulose prepared as above, Thiopropyl Sephorose 6B may be used which is a commercially available material supplied by Pharmacia Fine Chemicals.

As an alternative to the aqueous KCN elution solution used above, an aqueous 2.5 mM NaCN solution containing 2% by weight of NaNOs may be used.

Claims (6)

1. A method of separating lS5mAu from '95mug in a solution containing ions of '95mug, wherein l95mAu is generated by radioactive decay of'95mHg, which method comprises: (i) contacting the solution with vicinal dithiol cellulose thereby to adsorb the 195mHg++ ions from the solution onto the vicinal dithiol cellulose; and (ii) eluting from the vicinal dithiol cellulose, l95mAu arising from radioactive decay of the 195Hg by means of an eluting solution containing an eluting agent therefor.

2. A method according to claim 1 wherein the pH of the solution in step (i) is in the range of 1 to 9.

3. A method according to either of the preceding claims wherein the eluting agent is CN ion.

4. A method of separating l95mAu from 195mHg in a solution containing ions of 195mHg, wherein 195may is generated by radioactive decay of 195mHg, substantially as described herein with reference to any of the experiments in the example.

5.195mAu separated from 195mHg by a method according to any of the preceding claims.

6. An isotope generator for generating '95mAu comprising a separating column containing vicinal dithiol cellulose having 195mHg adsorbed thereon.