Synthesis and Characterization of Two PET Radioligands for the Metabotropic Glutamate 1 (mGlu1) Receptor YIYUN HUANG, 1,2 * RAJESH NARENDRAN, 1 FRANCOIS BISCHOFF, 3 NINGNING GUO, 1 SUNG A. BAE, 1 DAH-REN HWANG, 1,2 ANNE S. LESAGE, 4 AND MARC LARUELLE 1,2 1 Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York 2 Department of Radiology, Columbia University College of Physicians and Surgeons, New York, New York 3 Department of Medicinal Chemistry, Johnson & Johnson Pharmaceutical Research and Development, A Division of Janssen Pharmaceutica, N.V., Beerse, Belgium 4 CNS Discovery Research, Johnson & Johnson Pharmaceutical Research and Development, A Division of Janssen Pharmaceutica, N.V., Beerse, Belgium KEY WORDS Metabotropic glutamate receptor; Radioligand; Synthesis ABSTRACT The metabotropic glutamate 1 receptor (mGlu1) is an important pro- tein in the regulation of glutamate transmission in the brain, and believed to be involved in disorders such as ischemia, epilepsy, neuropathic pain, anxiety, and schizo- phrenia. 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 recep- tor. 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. Synapse 66:1002– 1014, 2012. V V C 2012 Wiley Periodicals, Inc. INTRODUCTION The metabotropic glutamate receptors (mGlu) are G-protein-coupled receptors in the central nervous sys- tem that regulate cell excitability and synaptic trans- mission (Conn and Pin, 1997). They are classified into three major groups with eight subtypes (Group I: mGlu1 and 5; Group II: mGlu2 and 3; Group III: mGlu4, 6, 7, and 8) based on their sequence homology, signal transduction mechanism, and pharmacology (Pin and Acher, 2002). The Group I metabotropic receptors, which encompass the mGlu1 and 5 sub- types, are mainly postsynaptic receptors and have been implicated in disorders such as ischemia, epilepsy, neuropathic pain, anxiety, and schizophrenia (Bordi and Ugolini, 1999; Conn, 2003; Moghaddam, 2004). Therefore, the Group I metabotropic receptors have been the targets of intensive drug development effort (Conn, 2003; Spooren et al., 2003). Contract grant sponsors: Johnson and Johnson Pharmaceutical Research and Development, A Division of Janssen Pharmaceutica, N.V., Beerse, Belgium *Correspondence to: Yiyun Huang, PO Box 208048, PET Center, Department of Diagnostic Radiology, Yale University School of Medicine, 801 Howard Ave- nue, New Haven, CT 06520-8048, USA. E-mail: henry.huang@yale.edu Received 20 June 2012; Accepted 20 August 2012 DOI 10.1002/syn.21606 Published online 28 August 2012 in Wiley Online Library (wileyonlinelibrary. com). SYNAPSE 66:1002–1014 (2012) V V C 2012 WILEY PERIODICALS, INC.