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

详细信息    查看全文

• 作者：Vincent Mé ; dran-Navarrete^a ; Annelaure Damont^a ; ^{annelaure.damont@cea.fr" class="auth_mail} ; Marie-Anne Peyronneau^a ; Bertrand Kuhnast^a ; Nicholas Bernards^a ; ^b ; Gé ; raldine Pottier^a ; ^b ; Frank Marguet^c ; Fré ; dé ; ric Puech^c ; Raphaë ; l Boisgard^a ; ^b ; Fré ; dé ; ric Dollé ; ^a
• 关键词：DPA-714 analogues ; TSPO 18  ; kDa ; Fluorinated ligands ; Metabolism ; PET imaging
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：15 March, 2014
• 年：2014
• 卷：24
• 期：6
• 页码：1550-1556
• 全文大小：1090 K

文摘

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-(蠅-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 (K_i vs [³H]PK11195: 0.35-0.79 nM; K_i vs [³H]flunitrazepam: >1000 nM) when compared to DPA-714 (K_i vs [³H]PK11195: 0.91 nM; K_i vs [³H]flunitrazepam: >1000 nM). Lipophilicities (HPLC, log D_7.4) 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.