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Article Dans Une Revue Nuclear Medicine and Biology Année : 2014

Synthesis and pharmacological evaluation of a new series of radiolabeled ligands for 5-HT7

Résumé

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 40-129 GBq/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.

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Dates et versions

hal-00947697 , version 1 (17-02-2014)

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J. Colomb, G. Becker, E. Forcellini, S. Meyer, L. Buisson, et al.. Synthesis and pharmacological evaluation of a new series of radiolabeled ligands for 5-HT7. Nuclear Medicine and Biology, 2014, 41 (4), pp.330-337. ⟨10.1016/j.nucmedbio.2014.01.008⟩. ⟨hal-00947697⟩
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