Referenced in: none

Automatically associated channels: Kir2.3 , Slo1

Title: Novel Pyrazolo[1,5-a]pyrimidines as Translocator Protein 18 kDa (TSPO) Ligands: Synthesis, in Vitro Biological Evaluation, [(18)F]-Labeling, and in Vivo Neuroinflammation PET Images.

Authors: Annelaure Damont, Vincent Médran-Navarrete, Fanny Cacheux, Bertrand Kuhnast, Géraldine Pottier, Nicholas Bernards, Frank Marguet, Frédéric Puech, Raphael Boisgard, Frédéric Dollé

Journal, date & volume: J. Med. Chem., 2015 Sep 24 , 58, 7449-64

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/26280386

Abstract
A series of novel pyrazolo[1,5-a]pyrimidines, closely related to N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide (2, DPA-714), were synthesized and biologically in vitro evaluated for their potential to bind the translocator protein 18 kDa (TSPO), a protein today recognized as an early biomarker of neuroinflammatory processes. This series is composed of fluoroalkyl- and fluoroalkynyl- analogues, prepared from a common iodinated intermediate via Sonogashira coupling reactions. All derivatives displayed subnanomolar affinity for the TSPO (0.37 to 0.86 nM), comparable to that of 2 (0.91 nM). Two of them were radiolabeled with fluorine-18, and their biodistribution was investigated by in vitro autoradiography and positron emission tomography (PET) imaging on a rodent model of neuroinflammation. Brain uptake and local accumulation of both compounds in the AMPA-mediated lesion confirm their potential as in vivo PET-radiotracers. In particular, [(18)F]23 exhibited a significantly higher ipsi- to contralateral ratio at 60 min than the parent molecule [(18)F]2 in vivo.