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01-07-2018 | Original Article

¹⁸F-F13640 preclinical evaluation in rodent, cat and primate as a 5-HT_1A receptor agonist for PET neuroimaging

Authors: Benjamin Vidal, Sylvain Fieux, Matthieu Colom, Thierry Billard, Caroline Bouillot, Olivier Barret, Cristian Constantinescu, Gilles Tamagnan, Adrian Newman-Tancredi, Luc Zimmer

Published in: Brain Structure and Function | Issue 6/2018

Abstract

Serotonin 1A receptors are known to play an important role in many psychiatric and neurodegenerative disorders. Currently, all available 5-HT_1A receptor PET radiopharmaceuticals that are radiolabeled with fluorine-18 are antagonists. As agonists bind preferentially to the high-affinity state of receptors, it would be of great interest to develop agonist radioligands which could provide a measure of the functional 5-HT_1A receptors in pathophysiological processes. The 5-HT_1A receptor agonist candidates we recently proposed had promising in vitro properties but were not optimal in terms of PET imaging. F13640, a.k.a befiradol or NLX-112, is a 5-HT_1A receptor agonist with a high affinity (Ki = 1 nM) and a high selectivity that would be suitable for a potential PET radiopharmaceutical. With propose here the first preclinical evaluation of ¹⁸F-F13640. ¹⁸F-F13640’s nitro-precursor was synthesized and radiolabeled via a fluoro-nucleophilic substitution. Its radiopharmacological characterization included autoradiographic studies, metabolic studies, and in vivo PET scans in rat, cat and non-human primate. Some of the results were compared with the radiotracer ¹⁸F-MPPF, a 5-HT_1A receptor antagonist. The radiochemical purity of ¹⁸F-F13640 was > 98%. In vitro binding pattern was consistent with the 5-HT_1A receptor distribution. Metabolic studies revealed that the radiotracer rapidly entered the brain and led to few brain radiometabolites. Although ¹⁸F-F13640 in vivo binding was blocked by the 5-HT_1A antagonist WAY-100635 and the 5-HT_1A agonist 8-OH-DPAT, the distribution pattern was markedly different from antagonist radiotracers in the three species, suggesting it provides novel information on 5-HT_1A receptors. Preliminary studies also suggest a high sensitivity of ¹⁸F-F13640 to endogenous serotonin release. ¹⁸F-F13640 has suitable characteristics for probing in vitro and in vivo the 5-HT_1A receptors in high-affinity state. Quantification analyses with kinetic modeling are in progress to prepare the first-in-man study of ¹⁸F-F13640.

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Title: 18F-F13640 preclinical evaluation in rodent, cat and primate as a 5-HT1A receptor agonist for PET neuroimaging
Authors: Benjamin Vidal
Sylvain Fieux
Matthieu Colom
Thierry Billard
Caroline Bouillot
Olivier Barret
Cristian Constantinescu
Gilles Tamagnan
Adrian Newman-Tancredi
Luc Zimmer
Publication date: 01-07-2018
Publisher: Springer Berlin Heidelberg
Published in: Brain Structure and Function / Issue 6/2018
Print ISSN: 1863-2653
Electronic ISSN: 1863-2661
DOI: https://doi.org/10.1007/s00429-018-1672-7

At a glance: The STEP trials

Springer Medicine

¹⁸F-F13640 preclinical evaluation in rodent, cat and primate as a 5-HT_1A receptor agonist for PET neuroimaging

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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