کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10586960 | 981411 | 2014 | 14 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Preparation and evaluation of novel pyrazolo[1,5-a]pyrimidine acetamides, closely related to DPA-714, as potent ligands for imaging the TSPO 18Â kDa with PET
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کلمات کلیدی
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
پیش نمایش صفحه اول مقاله
![عکس صفحه اول مقاله: Preparation and evaluation of novel pyrazolo[1,5-a]pyrimidine acetamides, closely related to DPA-714, as potent ligands for imaging the TSPO 18Â kDa with PET Preparation and evaluation of novel pyrazolo[1,5-a]pyrimidine acetamides, closely related to DPA-714, as potent ligands for imaging the TSPO 18Â kDa with PET](/preview/png/10586960.png)
چکیده انگلیسی
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-(Ï-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, log D7.4) 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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 24, Issue 6, 15 March 2014, Pages 1550-1556
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 24, Issue 6, 15 March 2014, Pages 1550-1556
نویسندگان
Vincent Médran-Navarrete, Annelaure Damont, Marie-Anne Peyronneau, Bertrand Kuhnast, Nicholas Bernards, Géraldine Pottier, Frank Marguet, Frédéric Puech, Raphaël Boisgard, Frédéric Dollé,