title: Synthesis and biological evaluation of potential 5-HT(7) receptor PET radiotracers.
abstract: Brain serotonin 7 receptor (5-HT(7)) 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-HT(7) receptor in vivo, our objective is to develop the first 5-HT(7) fluorine-18 labeled radiotracer. Four structural analogs of SB269970, a specific 5-HT(7) 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 [(18)F(-)]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-HT(7) receptors (pK(B)) between 7.8 and 8.8. The four PET radiotracers had suitable characteristic for 5-HT(7) 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.
authors.affiliation: Université de Lyon, Université Lyon 1, CNRS, Institute of Chemistry and Biochemistry (ICBMS - UMR CNRS 5246), 43 Bd du 11 novembre 1918, 69622 Lyon, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Andries
authors.forename: Laetitia
authors.initials: L
authors.lastname: Lemoine
authors.forename: Didier
authors.initials: D
authors.lastname: Le Bars
authors.forename: Luc
authors.initials: L
authors.lastname: Zimmer
authors.forename: Thierry
authors.initials: T
authors.lastname: Billard
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism; D005462:Fluorine Radioisotopes / Q000737:chemistry* / Q000378:metabolism; D008297:Male; D008867:Microtomy; D019964:Mood Disorders / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C104425:serotonin 7 receptor; D012701:Serotonin