[¹⁸F]R91150: Improved radiosynthesis and in vivo evaluation as imaging probe for 5-HT_2A receptors

Serotonergic 5-HT_2A receptors in the cortex and other forebrain structures have been linked to cognitive, emotional and memory processes. In addition, dysfunction or altered expression of these receptors is associated with neuropsychiatric and neurodegenerative disorders. [¹⁸F]R91150 is a candidate radiotracer for positron emission tomography (PET) imaging of 5-HT_2A receptors, which showed promising properties in in vitro studies. However, existing methods for the production of [¹⁸F]R91150 are rather inefficient and its imaging properties have not been studied in vivo. In the present work, we describe improved protocols for preparation of [¹⁸F]R91150, the corresponding reference compound and two alternative boronate radiolabeling precursors. Furthermore, we present the results of an in vivo evaluation of the radioligand in rodents. [¹⁸F]R91150 was prepared in activity yields of 20 ± 5% (two-step radiosynthesis) or 12 ± 2% (one-step radiosynthesis) and with molar activities of >200 GBq/μmol. μPET measurements in mice revealed sufficient stability against in vivo defluorination and predominantly hepatobiliary excretion of the tracer, with high radioactivity uptake in gall bladder and intestines. μPET imaging in rats demonstrated specific tracer accumulation in the cortex and subcortical forebrain structures, which could be reduced by pretreatment or displacement with the 5-HT_2A receptor ligands altanserin or ketanserin but was insensitive to pretreatment with the 5-HT_2C receptor ligand SB242084. In addition, [¹⁸F]R91150 showed specific accumulation in the choroid plexus that was much less sensitive to displacement with ketanserin and unaffected by pretreatment with altanserin or SB242084. Taken together, our results indicate that [¹⁸F]R91150 may be a promising candidate for in vivo PET imaging of cortical 5-HT_2A receptors, although further studies will be required to elucidate the mechanisms underlying tracer accumulation in the choroid plexus.