Development of New PET radiopharmaceuticals for imaging monoamine oxidase-B

Introduction: ImagingmonoamineoxidaseB(MAO-B)inthecentralnervoussystemwithPETisanimportantgoalforpsychiatricstudies.We here report an improved and automated radiosynthesis of N-(6-[ 18 F]-fluorohexyl)-N-methylpropargylamine ([ 18 F]FHMP; [ 18 F]-1), as well as the radiosynthesis of two new promising candidates for imaging cerebral MAO-B, namely, carbon-11-labeled 3-(4-[ 11 C]-methoxyphenyl)-6methyl-2H-1-benzopyran-2-one ([ 11 C]-2) and N-((1H-pyrrol-2-yl)methyl)-N-[ 11 C]-methyl-1-phenylmethanamine ([ 11 C]-3). Methods: Fluorine-18-labeled 1 was prepared via a tosyloxy precursor in 29%±5% uncorrected radiochemical yield, relative to [ 18 F]fluoride. Both carbon-11-labeled compounds were prepared with [ 11 C]CH3I using the “LOOP” method in 11% and 18% uncorrected radiochemical yields, respectively, relative to starting [ 11 C]CO2. All radiotracers had specific activities N37 GBq/μmol and were N98% radiochemically pure at end of synthesis (b40 min). All radiotracers were evaluated by ex vivo biodistribution studies in conscious rodents. Results: A major radioactive metabolite in the rodent brain was observed following administration of [ 18 F]-1. While [ 11 C]-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 [ 11 C]-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. Conclusion: Carbon-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.