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

Milicevic Sephton, Selena, Vetterli, Peter, Pedani, Valentina, Cermak, Stjepko, Chiotellis, Aristeidis, Schibli, Roger, Auberson, Yves and Ametamey, Simon (2017) Synthesis and Biological Evaluation of Quinoxaline Derivatives for PET Imaging of the NMDA Receptor. Helvetica Chimica Acta, 100 (12). ISSN 15222675


Due to the biological complexity of the N-methyl-d-aspartate receptor (NMDAR), the development of a positron emission tomography radiotracer for the imaging of NMDAR has met with limited success. Recent studies have established the presence of GluN2A subunit of the NMDAR in the heart and its role in the regulation of intracellular calcium levels. In our efforts to develop an imaging agent for the GluN2A subunit, we designed three new compounds based on a quinoxaline scaffold. The synthesis of the analogues was based on a two-step Kabachnik–Fields reaction in sequence with Suzuki cross-coupling and acid hydrolysis. They exhibited comparable high binding affinity values below 5 nm. A two-step radiolabeling procedure was successfully developed for the synthesis of [18F]1. [18F]1 was obtained in a modest overall radiochemical yield of 5.5 ± 4.2%, a good specific radioactivity of 254 ± 158 GBq/μmol, and a radiochemical purity > 99%. While compounds 2 and 3 showed comparable binding affinity towards NMDAR, sluggish radiolabeling, prevented their further evaluation. For [18F]1, in vitro autoradiography on rat heart slices demonstrated heterogeneous but unspecific accumulation, whereas for the brain a high in vitro specificity towards NMDAR, could be demonstrated.

Item Type: Article
Keywords: brain GluN2A subunit heart slices NMDA receptor PET imaging quinoxaline derivatives [18F]-labelling
Date Deposited: 07 Apr 2018 00:45
Last Modified: 25 Jan 2019 00:45