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.
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.
CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France.|Inserm/CEA/Université Paris Sud, UMR 1023-ERL 9218 CNRS, IMIV, Orsay, France.
Annelaure
A
Damont
CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France.|Inserm/CEA/Université Paris Sud, UMR 1023-ERL 9218 CNRS, IMIV, Orsay, France.
Vincent
V
Médran-Navarrete
CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France.|Inserm/CEA/Université Paris Sud, UMR 1023-ERL 9218 CNRS, IMIV, Orsay, France.
Fanny
F
Cacheux
CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France.|Inserm/CEA/Université Paris Sud, UMR 1023-ERL 9218 CNRS, IMIV, Orsay, France.
Bertrand
B
Kuhnast
CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France.|Inserm/CEA/Université Paris Sud, UMR 1023-ERL 9218 CNRS, IMIV, Orsay, France.
Géraldine
G
Pottier
CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France.|Inserm/CEA/Université Paris Sud, UMR 1023-ERL 9218 CNRS, IMIV, Orsay, France.
Nicholas
N
Bernards
LGCR, Sanofi, Chilly-Mazarin, France.
Frank
F
Marguet
LGCR, Sanofi, Chilly-Mazarin, France.
Frédéric
F
Puech
CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France.|Inserm/CEA/Université Paris Sud, UMR 1023-ERL 9218 CNRS, IMIV, Orsay, France.
Raphaël
R
Boisgard
CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France.|Inserm/CEA/Université Paris Sud, UMR 1023-ERL 9218 CNRS, IMIV, Orsay, France.
Frédéric
F
Dollé
D000081:Acetamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D004660:Encephalitis / Q000000981:diagnostic imaging / Q000378:metabolism; D005462:Fluorine Radioisotopes; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D049268:Positron-Emission Tomography; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000081:Acetamides; D002352:Carrier Proteins; D005462:Fluorine Radioisotopes; D006574:Heterocyclic Compounds, 2-Ring; D008024:Ligands; C530129:N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo(1,5-a)pyrimidin-3-yl)acetamide; C000603800:N,N-diethyl-2-(2-(4-(5-fluoropent-1-yn-1-yl)phenyl)-5,7-dimethylpyrazolo(1,5-a)pyrimidin-3-yl)acetamide; D011720:Pyrazoles; D011743:Pyrimidines; D019275:Radiopharmaceuticals; D011963:Receptors, GABA-A; C069997:Tspo protein, rat