Imaging the trace amine-associated receptor 1 by positron emission tomography

Abstract Trace amine-associated receptor 1 (TAAR1) has been implicated in drug addiction, schizophrenia, depression and Parkinson’s disease (PD). To date, there are no reports on TAAR1-targeted probes for non-invasive quantification of receptor density in vivo. Herein, we report the synthesis of a 11C-labeled TAAR1 high-affinity antagonist N-(3-methoxyphenyl)-6-(pyrrolidin-1-yl)-5-(trifluoromethyl)nicotinamide [11C]4 (also named [11C]TAAR1-1911), as well as its physicochemical and preclinical evaluations for positron emission tomography (PET) imaging. This PET ligand was afforded using [11C]CH3I with the base NaOH in good radiochemical yield (non-decay corrected 14% relative to starting [11C]CO2), excellent radiochemical purities (> 99%) and high molar activities (> 37 GBq/µmol). Despite promising in vitro performance characteristics, [11C]4 did not exhibit in vivo specificity, potentially owing to fast metabolic degradation. Further studies are warranted to identify a suitable TAAR1 PET tracer, which would ultimately aid the development of TAAR1-directed therapeutic agents.