title: Synthesis and characterization of two PET radioligands for the metabotropic glutamate 1 (mGlu1) receptor.
abstract: The metabotropic glutamate 1 receptor (mGlu1) is an important protein in the regulation of glutamate transmission in the brain, and believed to be involved in disorders such as ischemia, epilepsy, neuropathic pain, anxiety, and schizophrenia. The goal of this study was to evaluate two selective mGlu1 antagonists [(11) C]3 and [(18) F]4 as potential PET radioligands for the in vivo imaging of the mGlu1 receptor. Biodistribution studies in rats indicated high uptake of [(11) C]3 and [(18) F]4 in the brain. The highest activity level was found in the cerebellum, followed by striatum, hippocampus, frontal cortex, and medulla, in a pattern consistent with the distribution of mGlu1 receptor in rat. At 30 min postinjection, the activity ratio of cerebellum to medulla was 4.5 for [(11) C]3, indicating a high degree of specific binding, while specific binding was lower for [(18) F]4 (cerebellum to medulla activity ratio of 2.0). Moreover, binding of the radioligands [(11) C]3 and [(18) F]4 in mGlu1 receptor-rich region such as cerebellum was blocked by pretreatment of the rats with their respective unlabeled compound or the selective mGlu1 antagonist (compound 5, 2 mg/kg each), but not by the selective mGlu2 antagonist LY341495, or the selective mGlu5 antagonist MPEP (2 mg/kg), thus indicating the binding specificity and selectivity of [(11) C]3 and [(18) F]4 to the mGlu1 receptor. However, in imaging experiments in baboons [(11) C]3 displayed a small specific binding signal only in the cerebellum, while the specific binding of [(18) F]4 was difficult to detect. Species differences in receptor density and affinity of the radioligands in large part account for the differences in the behavior of [(11) C]3 and [(18) F]4 in rats and baboons. Radioligands with higher affinity and/or lower lipophilicity are needed to successfully image the mGlu1 receptor in humans.
authors.affiliation: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York, USA. henry.huang@yale.edu
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
authors.forename: Rajesh
authors.initials: R
authors.lastname: Narendran
authors.forename: Francois
authors.initials: F
authors.lastname: Bischoff
authors.forename: Ningning
authors.initials: N
authors.lastname: Guo
authors.forename: Sung A
authors.initials: SA
authors.lastname: Bae
authors.forename: Dah-Ren
authors.initials: DR
authors.lastname: Hwang
authors.forename: Anne S
authors.initials: AS
authors.lastname: Lesage
authors.forename: Marc
authors.initials: M
authors.lastname: Laruelle
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging; D016466:CHO Cells; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D006224:Cricetinae; D003412:Cricetulus; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D008024:Ligands; D008297:Male; D010215:Papio; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014018:Tissue Distribution; D014966:Xanthenes / Q000494:pharmacology
chemical_list: C578364:(3-ethyl-2-fluoro-6-quinolinyl)(4-methoxycyclohexyl)methanone; C502015:(3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxycyclohexyl)methanone methanesulfonate; D000596:Amino Acids; D002250:Carbon Radioisotopes; D018691:Excitatory Amino Acid Antagonists; D005462:Fluorine Radioisotopes; C114624:LY 341495; D008024:Ligands; D011725:Pyridines; D011804:Quinolines; D019275:Radiopharmaceuticals; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; C104077:metabotropic glutamate receptor type 1; C121465:6-methyl-2-(phenylethynyl)pyridine