Synthesis and Biological Evaluation of Quinoxaline Derivatives for PET Imaging of the NMDA Receptor

  1. Milicevic Sephton, Selena 1
  2. Vetterli, Peter T. 1
  3. Pedani, Valentina 1
  4. Cermak, Stjepko 1
  5. Chiotellis, Aris 1
  6. Roscales García, Silvia 1
  7. Müller Herde, Adrienne 1
  8. Schibli, Roger 12
  9. Auberson, Yves P. 3
  10. Ametamey, Simon M. 1
  1. 1 Department of Chemistry and Applied Biosciences; Center for Radiopharmaceutical Sciences of ETH, PSI and USZ; Swiss Federal Institute of Technology (ETH); Vladimir-Prelog-Weg 4 CH-8093 Zurich Switzerland
  2. 2 Center for Radiopharmaceutical Sciences of ETH, PSI and USZ; Paul-Scherrer Institute; Villigen CH-5232 Switzerland
  3. 3 Novartis Institutes for BioMedical Research; Novartis Pharma AG; CH-4002 Basel Switzerland
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Revista:
Helvetica Chimica Acta

ISSN: 1522-2675

Año de publicación: 2017

Volumen: 100

Número: 12

Páginas: e1700204

Tipo: Artículo

DOI: 10.1002/HLCA.201700204 GOOGLE SCHOLAR lock_openAcceso abierto editor

Otras publicaciones en: Helvetica Chimica Acta

Resumen

Due to the biological complexity of theN-methyl-D-aspartate receptor (NMDAR), the development of a positronemission tomography radiotracer for the imaging of NMDAR has met with limited success. Recent studies haveestablished the presence of GluN2A subunit of the NMDAR in the heart and its role in the regulation of intracellularcalcium levels. In our efforts to develop an imaging agent for the GluN2A subunit, we designed three newcompounds based on a quinoxaline scaffold. The synthesis of the analogues was based on a two-stepKabachnik–Fieldsreaction in sequence withSuzukicross-coupling and acid hydrolysis. They exhibited comparable high bindingaffinity values below 5 nM. A two-step radiolabeling procedure was successfully developed for the synthesis of [18F]1.[18F]1was obtained in a modest overall radiochemical yield of 5.54.2%, a good specific radioactivity of254158 GBq/lmol, and a radiochemical purity>99%. While compounds2and3showed comparable bindingaffinity towards NMDAR, sluggish radiolabeling, prevented their further evaluation. For [18F]1,in vitroautoradiographyon rat heart slices demonstrated heterogeneous but unspecific accumulation, whereas for the brain a highin vitrospecificity towards NMDAR, could be demonstrated.

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