title: Synthesis, evaluation, and radiolabeling of new potent positive allosteric modulators of the metabotropic glutamate receptor 2 as potential tracers for positron emission tomography imaging.
abstract: The synthesis and in vitro and in vivo evaluation of a new series of 7-(phenylpiperidinyl)-1,2,4-triazolo[4,3-a]pyridines, which were conveniently radiolabeled with carbon-11, as potential positron emission tomography (PET) radiotracers for in vivo imaging of the allosteric binding site of the metabotropic glutamate (mGlu) receptor subtype 2 are described. The synthesized compounds proved to be potent and selective positive allosteric modulators (PAMs) of the mGlu receptor 2 (mGluR2) in a [³⁵S]GTPγS binding assay and were able to displace an mGluR2 PAM radioligand, which we had previously developed, with IC₅₀ values in the low nanomolar range. The most promising candidates were radiolabeled and subjected to biodistribution studies and radiometabolite analysis in rats. Preliminary small-animal PET (μPET) studies in rats indicated that [¹¹C]20f binds specifically and reversibly to an mGluR2 allosteric site, strongly suggesting that it is a promising candidate for PET imaging of mGluR2 in the brain.
authors.affiliation: Medicinal Chemistry, Janssen Research & Development , Janssen-Cilag S.A., C/Jarama 75, 45007 Toledo, Spain. iandres@its.jnj.com
authors.forename: José-Ignacio
authors.initials: JI
authors.lastname: Andrés
authors.forename: Jesús
authors.initials: J
authors.lastname: Alcázar
authors.forename: José María
authors.initials: JM
authors.lastname: Cid
authors.forename: Meri
authors.initials: M
authors.lastname: De Angelis
authors.forename: Laura
authors.initials: L
authors.lastname: Iturrino
authors.forename: Xavier
authors.initials: X
authors.lastname: Langlois
authors.forename: Hilde
authors.initials: H
authors.lastname: Lavreysen
authors.forename: Andrés A
authors.initials: AA
authors.lastname: Trabanco
authors.forename: Sofie
authors.initials: S
authors.lastname: Celen
authors.forename: Guy
authors.initials: G
authors.lastname: Bormans
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D002250:Carbon Radioisotopes; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008297:Male; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D002250:Carbon Radioisotopes; D011725:Pyridines; D019275:Radiopharmaceuticals; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; C108822:metabotropic glutamate receptor 2