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

J Med Chem. 2016 Dec 22;59(24):11110-11119. doi: 10.1021/acs.jmedchem.6b01344. Epub 2016 Dec 6.

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 [124/125I]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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites / drug effects
  • Brain / diagnostic imaging*
  • Carbon Radioisotopes
  • Dose-Response Relationship, Drug
  • Glutamic Acid / chemistry*
  • Iodine Radioisotopes
  • Ligands
  • Male
  • Mice
  • Mice, Nude
  • Molecular Structure
  • Neuroprotective Agents / chemistry*
  • Neuroprotective Agents / pharmacology
  • Positron Emission Tomography Computed Tomography
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacology
  • Receptors, N-Methyl-D-Aspartate / analysis*
  • Structure-Activity Relationship

Substances

  • Carbon Radioisotopes
  • Iodine Radioisotopes
  • Ligands
  • Neuroprotective Agents
  • Pyrazoles
  • Receptors, N-Methyl-D-Aspartate
  • Glutamic Acid