This projects objective is to establish the technicalfeasibility of an automated process for the enzymatic synthesis andsubsequent purification of radiopharmaceuticals-in particular, ofcarbon-11 ("C) thymidine and thymidine analogs such as3'-azidothymidine (AZT). The approach is based on usingmicroporous membranes both to immobilize the synthetic enzymesinvolved and to recover the reaction product in purified form. This membrane system approach to the production ofpositron-emitting radiopharmaceuticals has the potential forsignificantly reducing the total synthesis/purification time, whichis particularly important for a radionuclide such as "C with a 20.4minite half-life. By conducting reaction and separation withhigher yields in automated apparatus, technician safety can beenhanced significantly. Specifically, in Phase I a porous membranewill serve as a solid-phase support for thymidylate synthetase;this e catalyzes the production of "C deoxythymidine monophosphate from deoxyuridine with incorporation of a "C labelderived from 'IC formaldehyde in the process. Enzymeimmobilization obviates the need for separating the biocatalystfrom the reaction mixture, while the ability to supply reactants tothe immobilized enzyme by convective flow of solution into andthrough the microporous support membrane eliminates diffusionalresistances that would otherwise slow the reaction kinetics. Theresulting product mixture will be purified on line in a cyclicaffinity membrane process based on flow of product solution througha suitably absorptive and selective microporous membrane. Thus,the affinity purification techniques combine to provide highseparation factors with the characteristic speed and productivityof membrane separations.Anticipated Results/Potential Commercial Applications as described by the awardee:Successful completion of Phase I and II will result in improved methods and apparatus for the automatedsynthesis and purification of shortlived positron-emittingradiopharmaceuticals. The membrane-based system promises higherreaction and purification yields than can currently be achievedwith short half-life radioisotopes. The membrane approach mayextend the range of applications for which the use of suchcompounds may be considered feasible, and it should make nuclearmedicine based on such compounds safer for the technician and moreradionuclide efficient. Specific synthetic targets include thepreparation of such tumor imaging agents as "C-labelled thymidineas well as imaging agents for such antivirals as "C AZT.
