Characterization of the serotonin 2A receptor selective PET tracer (R)-[18F]MH.MZ in the human brain

Purpose The serotonin receptor subtype 2A antagonist (5-HT2AR) (R)-[F-18]MH.MZ has in preclinical studies been identified as a promising PET imaging agent for quantification of cerebral 5-HT(2A)Rs. It displays a very similar selectivity profile as [C-11]MDL 100907, one of the most selective compounds identified thus far for the 5-HT2AR. As [C-11]MDL 100907, (R)-[F-18]MH.MZ also displays slow brain kinetics in various animal models; however, the half-life of fluorine-18 allows for long scan times and consequently, a more precise determination of 5-HT2AR binding could still be feasible. In this study, we aimed to evaluate the potential of (R)-[F-18]MH.MZ PET to image and quantify the 5-HT2AR in the human brain in vivo. Methods Nine healthy volunteers underwent (R)-[F-18]MH.MZ PET at baseline and four out of these also received a second PET scan, after ketanserin pretreatment. Regional time-activity curves of 17 brain regions were analyzed before and after pretreatment. We also investigated radiometabolism, time-dependent stability of outcomes measures, specificity of (R)-[F-18]MH.MZ 5-HT2AR binding, and performance of different kinetic modeling approaches. Results Highest uptake was determined in 5-HT2AR rich regions with a BPND of approximately 1.5 in cortex regions. No radiometabolism was observed. 1TCM and 2TCM resulted in similar outcome measure, whereas reference tissue models resulted in a small, but predictable bias. (R)-[F-18]MH.MZ binding conformed to the known distribution of 5-HT2AR and could be blocked by pretreatment with ketanserin. Moreover, outcomes measures were stable after 100-110 min. Conclusion (R)-[F-18]MH.MZ is a suitable PET tracer to image and quantify the 5-HT2AR system in humans. In comparison with [C-11]MDL 100907, faster and more precise outcome measure could be obtained using (R)-[F-18]MH.MZ. We believe that (R)-[F-18]MH.MZ has the potential to become the antagonist radiotracer of choice to investigate the human 5-HT2AR system.