title: 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.
abstract: 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-(ω-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 18kDa (Ki vs [(3)H]PK11195: 0.35-0.79nM; Ki vs [(3)H]flunitrazepam: >1000nM) when compared to DPA-714 (Ki vs [(3)H]PK11195: 0.91nM; Ki vs [(3)H]flunitrazepam: >1000nM). 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.
authors.affiliation: CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Médran-Navarrete
authors.affiliation: CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France. Electronic address: annelaure.damont@cea.fr.
authors.forename: Annelaure
authors.initials: A
authors.lastname: Damont
authors.affiliation: CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Peyronneau
authors.affiliation: CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Kuhnast
authors.affiliation: CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France; Inserm, U1023, Université Paris Sud, Orsay, France.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Bernards
authors.affiliation: CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France; Inserm, U1023, Université Paris Sud, Orsay, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Pottier
authors.affiliation: Exploratory Unit, Sanofi, Chilly-Mazarin, France.
authors.forename: Frank
authors.initials: F
authors.lastname: Marguet
authors.affiliation: Exploratory Unit, Sanofi, Chilly-Mazarin, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Puech
authors.affiliation: CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France; Inserm, U1023, Université Paris Sud, Orsay, France.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Boisgard
authors.affiliation: CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Dollé
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging; D005462:Fluorine Radioisotopes / Q000737:chemistry; D008024:Ligands; D008861:Microsomes / Q000378:metabolism; D049268:Positron-Emission Tomography; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry; D051381:Rats
chemical_list: D000081:Acetamides; D005462:Fluorine Radioisotopes; D008024:Ligands; C530129:N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo(1,5-a)pyrimidin-3-yl)acetamide; D011720:Pyrazoles; D011743:Pyrimidines; D019275:Radiopharmaceuticals; C527752:pyrazolo(1,5-a)pyrimidine
keywords: DPA-714 analogues; Fluorinated ligands; Metabolism; PET imaging; TSPO 18kDa