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Preparation and evaluation of novel pyrazolo[1,5-a]pyrimidine acetamides, closely related to DPA-714, as potent ligands for imaging the TSPO 18 kDa with PET

Médran-Navarrete, Vincent; Damont, Annelaure; Peyronneau, Marie-Anne; Kuhnast, Bertrand; Bernards, Nicholas; Pottier, Géraldine; Marguet, Frank; Puech, Frédéric; Boisgard Raphael; Dollé, Frédéric

A series of four novel analogues of DPA-714, bearing a fluoroalkynyl side chain (with a length ranging from three to six carbon atoms) in replacement of the fluoroethoxy motif, have been synthetized in six steps from commercially available methyl 4-iodobenzoate. The synthetic strategy for the preparation of these N,N-diethyl-2-(2-(4-(x-fluoroalk-1-ynyl)phenyl)-5,7 dimethylpyrazolo[1,5-a]pyrimidin-3- yl)acetamides (7a–d) consisted in derivatizing a key iodinated building block featuring the pyrazolopyrimidine acetamide backbone of DPA-714, by Sonogashira couplings with various alkynyl reagents. The resulting alkynols were subsequently fluorinated, yielding the expected target derivatives. All four analogues exhibited slightly higher affinity and selectivity towards the TSPO 18 kDa (Ki vs [3H]PK11195: 0.35–0.79 nM; Ki vs [3H]flunitrazepam: >1000 nM) when compared to DPA-714 (Ki vs [3H]PK11195: 0.91 nM; Ki vs [3H]flunitrazepam: >1000 nM). Lipophilicities (HPLC, logD7.4) increased with the chain length (from 3.6 to 4.3) and were significantly higher than the one determined for DPA-714 (2.9). Preliminary in vitro metabolism evaluation using rat microsomal incubations and LC–MS analyses showed, for all four novel analogues, the absence of defluorinated metabolites. Among them, the fluoropentynyl compound, DPA-C5yne (7c), was selected, labelled in one single step with fluorine-18 from the corresponding tosylate and in vivo evaluated with PET on our in-house-developed rat model of acute local neuroinflammation.

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