Development of new radiopharmaceuticals for imaging monoamine oxidase B

IntroductionImaging monoamine oxidase B (MAO-B) in the central nervous system with PET is an important goal for psychiatric studies. We here report an improved and automated radiosynthesis of N-(6-[18F]-fluorohexyl)-N-methylpropargylamine ([18F]FHMP; [18F]-1), as well as the radiosynthesis of two new promising candidates for imaging cerebral MAO-B, namely, carbon-11-labeled 3-(4-[11C]-methoxyphenyl)-6-methyl-2H-1-benzopyran-2-one ([11C]-2) and N-((1H-pyrrol-2-yl)methyl)-N-[11C]-methyl-1-phenylmethanamine ([11C]-3).MethodsFluorine-18-labeled 1 was prepared via a tosyloxy precursor in 29%±5% uncorrected radiochemical yield, relative to [18F]-fluoride. Both carbon-11-labeled compounds were prepared with [11C]CH3I using the “LOOP” method in 11% and 18% uncorrected radiochemical yields, respectively, relative to starting [11C]CO2. All radiotracers had specific activities >37 GBq/μmol and were >98% radiochemically pure at end of synthesis (<40 min). All radiotracers were evaluated by ex vivo biodistribution studies in conscious rodents.ResultsA major radioactive metabolite in the rodent brain was observed following administration of [18F]-1. While [11C]-2 had moderate brain penetration and good clearance from normal brain tissue, distribution of radioactivity in brain was indicative of free and nonspecific binding. Good brain uptake was observed with [11C]-3 (0.8%–1.4% injected dose per gram at 5 min postinjection), binding appeared to be reversible and distribution conformed with regional distribution of MAO-B in the rat brain. Preinjection of 3 or l-deprenyl showed a modest reduction (up to 25%) of brain activity.ConclusionCarbon-11-labeled 3 was found to have the most favorable properties of the radiotracers evaluated; however, the signal-to-noise ratio was too low to warrant further in vivo imaging studies. Alternative radiotracers for imaging MAO-B are under development.