Synthesis and pharmacological evaluation of a new series of radiolabeled ligands for 5-HT7 receptor PET neuroimaging.

INTRODUCTION: The brain serotonin-7 receptor (5-HT7) is the most recently discovered serotonin receptor. It is targeted by several drug-candidates in psychopharmacology and neuropharmacology. In these fields, positron emission tomography (PET) is a molecular imaging modality offering great promise for accelerating the development process from preclinical discovery to clinical phases. We recently described fluorinated 5-HT7 radioligands, inspired by the structure of SB269970, the prototypical 5-HT7 antagonist. Although these results were promising, it appeared that the radiotracer-candidates suffered, among other drawbacks, from too low a 5-HT7 receptor affinity.

METHODS: In the present study, seven structural analogs of SB269970 were synthesized using design strategies aiming to improve their radiopharmacological properties. Their 5-HT7 binding properties were investigated by cellular functional assay. The nitro-precursors of the analogs were radiolabeled by [(18)F-]nucleophilic substitution, and in vitro autoradiography was performed in rat brain, followed by in vivo microPET.

RESULT: The chemical and radiochemical purity of the fluorine radiotracers was>99% with specific activity in the 40-129GBq/μmol range. The seven derivatives presented heterogeneous binding affinities toward 5-HT7 and 5-HT1A receptors. While [(18)F]2F3P3 had promising characteristics in vitro, it showed poor brain penetration in vivo, partially reversed after pharmacological inhibition of P-glycoprotein.

CONCLUSIONS: These results indicated that, while chemical modification of these series improved several radiotracer-candidates in terms of 5-HT7 receptor affinity and specificity toward 5-HT1A receptors, other physicochemical modulations would be required in order to increase brain penetration.