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

Lucia Tamborini, Ying Chen, Catherine Foss, Andrea Pinto, Andrew Horti, Stephen F. Traynelis, Carlo De Micheli, Ronnie Mease, Kasper B. Hansen, Paola Conti, Martin Gilbert Pomper

Research output: Contribution to journalArticle


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 [124/125I]4d and [11C]4e (i.e., [124/125I]11d and [11C]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 [125I]11d and [11C]11e through autoradiography and biodistribution studies, imaging of neither [124I]11d nor [11C]11e could demonstrate brain penetration sufficient for detection by PET.

Original languageEnglish (US)
Pages (from-to)11110-11119
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number24
StatePublished - Dec 22 2016


ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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