Synthesis and in vivo Evaluation of Fluorine-18 and Iodine-123 Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine Derivatives as PET and SPECT Radiotracers for Mapping A2AReceptors

Christine Vala, Thomas J. Morley*, Xuechun Zhang, Caroline Papin, Adriana Alexandre S. Tavares, H. Sharon Lee, Cristian Constantinescu, Olivier Barret, Vincent M. Carroll, Ronald M. Baldwin, Gilles D. Tamagnan, David Alagille

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Imaging agents that target adenosine type 2A (A2A) receptors play an important role in evaluating new pharmaceuticals targeting these receptors, such as those currently being developed for the treatment of movement disorders like Parkinson′s disease. They are also useful for monitoring progression and treatment efficacy by providing a noninvasive tool to map changes in A2Areceptor density and function in neurodegenerative diseases. We previously described the successful evaluation of two A2A-specific radiotracers in both nonhuman primates and in subsequent human clinical trials: [123I]MNI-420 and [18F]MNI-444. Herein we describe the development of both of these radiotracers by selection from a series of A2Aligands, based on the pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine core of preladenant. Each of this series of 16 ligands was found to bind to recombinant human A2Areceptor in the low nanomolar range, and of these 16, six were radiolabeled with either fluorine-18 or iodine-123 and evaluated in nonhuman primates. These initial in vivo results resulted in the identification of 7-(2-(4-(4-(2-[18F]fluoroethoxy)phenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine ([18F]MNI-444) and 7-(2-(4-(2-fluoro-4-[123I]iodophenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-amine ([123I]MNI-420) as PET and SPECT radiopharmaceuticals for mapping A2Areceptors in brain.

Original languageEnglish
Pages (from-to)1936-1943
Number of pages8
JournalChemMedChem
DOIs
Publication statusPublished - 1 Jan 2016

Keywords

  • adenosine 2A receptor
  • movement disorders
  • Parkinson′s disease
  • PET
  • SPECT

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