Development of Radiolabeled Ligands Targeting the Glutamate Binding Site of the N-Methyl-D-aspartate Receptor as Potential Imaging Agents for Brain

• Authors: Lucia Tamborini, University of Milan; Ying Chen, Johns Hopkins Medical School; Catherine A. Foss, Johns Hopkins Medical School; Andrea Pinto, University of Milan; Andrew G. Horti, Johns Hopkins Medical School; Stephen Traynelis, Emory University; Carlo De Micheli, University of Milan; Ronnie C. Mease, Johns Hopkins Medical School; Kasper B. Hansen, University of Montana; Paola Conti, University of Milan; Martin G. Pomper, Johns Hopkins Medical School
• Journal Title: Journal of Medicinal Chemistry
• Volume: Volume 59, Number 24
• Publisher: American Chemical Society | 2016-12-22, Pages 11110-11119
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1021/acs.jmedchem.6b01344
• Subjects: Health Sciences, Pharmacology; Health Sciences, Radiology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Chemistry, Medicinal; Pharmacology & Pharmacy; PHARMACOLOGICAL CHARACTERIZATION; NMDA RECEPTORS; PET RADIOLIGANDS; AMINO-ACIDS; ANTAGONISTS; AFFINITY; SUBTYPES; CHANNEL; DESIGN

Abstract

Abnormal activity of various N-methyl-d-aspartate receptor (NMDAR) subtypes has been implicated in a wide variety of neurological disorders such as Alzheimer's disease, schizophrenia, and epilepsy. Imaging agents for PET and SPECT that target NMDARs in a subtype-selective fashion may enable better characterization of those disorders and enhance drug development. On the basis of a pyrazoline derivative that demonstrated neuroprotective effects in vivo, we synthesized a series of para-substituted analogues and measured their affinities to various NMDAR subtypes. Compounds 4a-c and 4e showed greater, nanomolar affinity for the GluN1/2A subtype versus GluN1/2B. Dicarbomethoxy (pro-drug) analogues of [ 124/125 I]4d and [ 11 C]4e (i.e., [ 124/125 I]11d and [ 11 C]11e) were generated and tested for NMDAR binding specificity in ex vivo autoradiography and brain biodistribution studies. Although NMDAR-specific binding could be demonstrated for [ 125 I]11d and [ 11 C]11e through autoradiography and biodistribution studies, imaging of neither [ 124 I]11d nor [ 11 C]11e could demonstrate brain penetration sufficient for detection by PET.