Synthesis and biological evaluation of potential 5-HT7 receptor PET radiotracers

Brain serotonin 7 receptor (5-HT7) is involved in several mood disorders and drug candidates targeting this subtype are currently in development. Positron emission tomography (PET) is a molecular imaging modality offering great promise for accelerating the process from preclinical discovery to clinical phases. As no PET radiopharmaceutical has yet been used successfully to study the 5-HT7 receptor in vivo, our objective is to develop the first 5-HT7 fluorine-18 labeled radiotracer.Four structural analogs of SB269970, a specific 5-HT7 receptor antagonist, divided in FP3 series and FPMP series were synthesized. Their antagonist effects were investigated by cellular functional assay. Nitro-precursors of these analogs were radiolabeled via a [18F−]nucleophilic substitution and in vitro autoradiographies were performed in rat brain.Chemical and radiochemical purities of fluorine radiotracers were >99% with specific activities in 40–129 GBq/μmole range. The four derivates presented antagonism potencies toward 5-HT7 receptors (pKB) between 7.8 and 8.8. The four PET radiotracers had suitable characteristic for 5-HT7 receptor probing in vitro even if the FP3 series seemed to be more specific for this receptor. These results encourage us to pursue in vivo studies.

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► We design four ligands of 5-HT7 receptor.
► These ligands were radiolabelled with fluorine-18.
► In vitro and in vivo evaluation have been performed.
► These radioligands present good properties for PET imaging.