AN AUTOMATED MEMBRANE SYSTEM FOR RAPID SYNTHESIS AND PURIFICATION OF SHORT HALF-LIFE RADIOPHARMACEUTICALS

THE OBJECTIVE OF THIS RESEARCH PROJECT IS TO ESTABLISH THE TECHNICAL FEASIBILITY OF AN AUTOMATED PROCESS FOR THE ENZYMATIC SYNTHESIS AND SUBSEQUENT PURIFICATION OF RADIOPHARMACEUTICALS -- IN PARTICULAR, OF CARBON-11 THYMIDINE AND THYMIDINE ANALOGS SUCH AS AZT. OUR APPROACH IS BASED ON THE USE OF MICROPOROUS MEMBRANES BOTH TO IMMOBILIZE THE SYNTHETIC ENZYMES INVOLVED AND TO RECOVER THE REACTION PRODUCT IN PURIFIED FORM. THIS MEMBRANE SYSTEM APPROACH TO THE PRODUCTION OF POSITRON-EMITTING RADIOPHARMACEUTICALS HAS THE POTENTIAL FOR SIGNIFICANTLY REDUCING THE TOTAL SYNTHESIS/PURIFICATION TIME, WHICH IS PARTICULARLY IMPORTANT FOR A RADIONUCLIDE SUCH AS CARBON-11 WITH A 20.4 MINUTE HALF-LIFE. BY CONDUCTING REACTION AND SEPARATION WITH HIGHER YIELDS IN AUTOMATED APPARATUS, TECHNICIAN SAFETY CAN BE SIGNIFICANTLY ENHANCED. SPECIFICALLY, A POROUS MEMBRANE WILL SERVE AS A SOLID-PHASE SUPPORT FOR THYMIDYLATE SYNTHETASE (T.S.), WHICH ENZYME CATALYZES THE PRODUCTION OF C-11 DEOXYTHYMIDINE MONOPHOSPHATE (DTMP) FROM DEOXYURIDINE (DUMP), WITH INCORPORATION OF A CARBON-11 LABEL DERIVED FROM C-11 FORMALDEHYDE IN THE PROCESS. ENZYME IMMOBILIZATION OBVIATESTHE NEED FOR SEPARATING THE BIOCATALYST FROM THE REACTION MIXTURE, WHILE THE ABILITY TO SUPPLY REACTANTS TO THE IMMOBILIZED ENZYME BY CONVECTIVE FLOW OF SOLUTION INTO AND THROUGH THE MICROPOROUS SUPPORT MEMBRANE ELIMINATES DIFFUSIONAL RESISTANCES THAT WOULD OTHERWISE SLOW THE REACTION KINETICS. THE RESULTING PRODUCT MIXTURE WILL BE PURIFIED ON-LINE IN A CYCLIC AFFINITY MEMBRANE PROCESS BASEDON FLOW OF PRODUCT SOLUTION THROUGH A SUITABLY ADSORPTIVE AND SELECTIVE MICROPOROUS MEMBRANE -- THUS COMBINING THE ABILITY OF AFFINITY PURIFICATION TECHNIQUES TO PROVIDE HIGH SEPARATION FACTORS WITH THE CHARACTERISTIC SPEED AND PRODUCTIVITY OF MEMBRANE SEPARATIONS.