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Author Notes:

Corresponding Authors: For P.C.: phone, (+39)02-50319329; fax, (+39)02-50319326; paola.conti@unimi.it. For K.B.H.: phone, (+1)406-243-4820; kasper.hansen@mso.umt.edu. For M.G.P: phone, (+1)410-955-2789; mpomper@jhmi.edu

The manuscript was written through contributions of all authors.

All authors have given approval to the final version of the manuscript.

The technical assistance of Birgitte Nielsen is gratefully acknowledged.

The authors declare the following competing financial interest(s): Stephen F. Traynelis is a co-founder of NeurOp Inc, is the PI on a research grant to Emory from Janssen, and is a paid consultant for NeurOp, Janssen, and Pfizer.

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Research Funding:

This work was supported by National Institutes of Health (P20GM103546 and R01NS097536 to K.B.H., R01NS065371 to S.F.T., and R01CA134675 to M.G.P.).

A.P. acknowledges the financial support to the present research by the University of Milan (Piano di Sostegno alla Ricerca 2015/ 2017-Linea 2A).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Chemistry, Medicinal
  • Pharmacology & Pharmacy
  • PHARMACOLOGICAL CHARACTERIZATION
  • NMDA RECEPTORS
  • PET RADIOLIGANDS
  • AMINO-ACIDS
  • ANTAGONISTS
  • AFFINITY
  • SUBTYPES
  • CHANNEL
  • DESIGN

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

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Journal Title:

Journal of Medicinal Chemistry

Volume:

Volume 59, Number 24

Publisher:

, Pages 11110-11119

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2016 American Chemical Society.

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