Journal article Open Access

Novel pyrazolo[1,5-a]pyrimidines as translocator protein 18 kDa (TSPO) ligands: Synthesis, in vitro biological evaluation, [18F]-labelling and in vivo neuroinflammation PET images.

Damont, Annelaure; Medran-Navarrete, Vincent; Cacheux, Fanny; Kuhnast, Bertrand; Pottier, Géraldine; Bernards, Nicholas; Marguet, Frank; Puech, Frédéric; Boisgard, Raphael; Dollé, Frédéric

A series of novel pyrazolo[1,5-a]pyrimidines, closely related to N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide (2, DPA-714), were synthesized and biologically in vitro evaluated for their potential to bind the translocator protein 18 kDa (TSPO), a protein today recognized as an early biomarker of neuroinflammatory processes. This series is composed of fluoroalkyl- and fluoroalkynyl- analogues, prepared from a common iodinated intermediate via Sonogashira coupling reactions. All derivatives displayed subnanomolar affinity for the TSPO (0.37 to 0.86 nM), comparable to that of 2 (0.91 nM). Two of them were radiolabeled with fluorine-18, and their biodistribution was investigated by in vitro autoradiography and positron emission tomography (PET) imaging on a rodent model of neuroinflammation. Brain uptake and local accumulation of both compounds in the AMPA-mediated lesion confirm their potential as in vivo PET-radiotracers. In particular, [(18)F]23 exhibited a significantly higher ipsi- to contralateral ratio at 60 min than the parent molecule [(18)F]2 in vivo.

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