Synthesis and biological evaluation of potential 5-HT(7) receptor PET radiotracers |
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Authors: | Andries Julien Lemoine Laetitia Le Bars Didier Zimmer Luc Billard Thierry |
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Institution: | a 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 b Université de Lyon, Université Lyon 1, CNRS UMR5292, INSERM U1028, Lyon Neuroscience Research Center, 59 Bd Pinel, 69003 Lyon, France c CERMEP-Imagerie du Vivant, 59 Bd Pinel, 69003 Lyon, France d Hospices Civils de Lyon, 59 Bd Pinel, 69003 Lyon, France |
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Abstract: | 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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Keywords: | PET Serotonin 5-HT7 Fluorine-18 Homoproline |
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