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

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