Radiosyntheses and Preclinical Evaluation of Two N-(3-[11C]methylthiophenyl)-2-picolinamide ([11C]ML128) Derivatives As Radiotracers for Mglu4

1169 Objectives Metabotropic glutamate receptor subtype 4 (mGlu4) has been considered a therapeutic target for Parkinson’s disease and L-DOPA treatment induced dyskinesia to control synaptic glutamate transport. We have developed several allosteric modulators as PET imaging ligands for mGlu4. Now we introduce two derivatives of [11C]ML128, a previously reported PET imaging ligand. We hypothesize that introduction of methylthio functional group instead of methoxy group might improve pharmacokinetic properties and binding properties to mGlu4. Methods We prepared the mercaptophenyl precursors for two derivatives of N-(3-[11C]methylthiophenyl)-2-picolinamide, [11C]KALB012 and [11C]KALB016, by five step syntheses, and nonradioactive standards by methylation of the mercaptophenyl precursors. Subsequently, [11C]KALB012 and [11C]KALB016 were obtained using [11C]iodomethane mediated by 5 M potassium carbonate solution. Dynamic PET imaging (60 min) was done in six male Sprague-Dawley rats for baseline studies followed by blocking studies with N-(3-difluoromethoxyphenyl)-2-picolinamide hydrochloride salt (10 mg/kg i.v.) administered 1 min before the radiotracer. Results [11C]KALB012 and [11C]KALB016 were obtained with 27% and 44% radiochemical yield respectively and 98% radiochemical purities. The micro-PET images of [11C]KALB012 and [11C]KALB016 showed highest accumulation of both ligands in thalamus, hippocampus, striatum, and some accumulation in cerebellum. However, those images also showed fast uptake and washout in brain within 20 minutes. Of these two ligands [11C]KALB012 indicated better blocking effect than [11C]KALB016. Conclusions Although the pharmacokinetic properties were not improved from the previously reported [11C]ML128, [11C]KALB012 clearly indicated better specificity as a PET radiotracer than [11C]KALB016 or [11C]ML128. Research Support NIBIB-R01EB012864 and NIMH-R01MH91684 to ALB