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

Annelaure Damont; Vincent Médran-Navarrete; Fanny Cacheux; Bertrand Kuhnast; Géraldine Pottier; Nicholas Bernards; Frank Marguet; Frédéric Puech; Raphaël Boisgard; Frédéric Dollé

doi:10.1021/acs.jmedchem.5b00932

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

J Med Chem. 2015 Sep 24;58(18):7449-64. doi: 10.1021/acs.jmedchem.5b00932. Epub 2015 Sep 3.

Authors

Annelaure Damont^{1

2}, Vincent Médran-Navarrete^{1

2}, Fanny Cacheux^{1

2}, Bertrand Kuhnast^{1

2}, Géraldine Pottier^{1

2}, Nicholas Bernards^{1

2}, Frank Marguet³, Frédéric Puech³, Raphaël Boisgard^{1

2}, Frédéric Dollé^{1

2}

Affiliations

¹ CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France.
² Inserm/CEA/Université Paris Sud, UMR 1023-ERL 9218 CNRS, IMIV, Orsay, France.
³ LGCR, Sanofi, Chilly-Mazarin, France.

PMID: 26280386
DOI: 10.1021/acs.jmedchem.5b00932

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetamides / chemistry*
Acetamides / pharmacokinetics
Acetamides / pharmacology
Animals
Autoradiography
Binding, Competitive
Brain / diagnostic imaging*
Brain / metabolism
Carrier Proteins / metabolism*
Encephalitis / diagnostic imaging
Encephalitis / metabolism
Fluorine Radioisotopes
Heterocyclic Compounds, 2-Ring / chemistry*
Heterocyclic Compounds, 2-Ring / pharmacokinetics
Heterocyclic Compounds, 2-Ring / pharmacology
Humans
In Vitro Techniques
Ligands
Male
Mice
Microsomes, Liver / metabolism
Positron-Emission Tomography
Protein Binding
Pyrazoles / chemistry*
Pyrazoles / pharmacokinetics
Pyrazoles / pharmacology
Pyrimidines / chemistry*
Pyrimidines / pharmacokinetics
Pyrimidines / pharmacology
Radioligand Assay
Radiopharmaceuticals / chemistry*
Radiopharmaceuticals / pharmacokinetics
Radiopharmaceuticals / pharmacology
Rats, Sprague-Dawley
Rats, Wistar
Receptors, GABA-A / metabolism*
Structure-Activity Relationship

Substances

Acetamides
Carrier Proteins
Fluorine Radioisotopes
Heterocyclic Compounds, 2-Ring
Ligands
N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo(1,5-a)pyrimidin-3-yl)acetamide
N,N-diethyl-2-(2-(4-(5-fluoropent-1-yn-1-yl)phenyl)-5,7-dimethylpyrazolo(1,5-a)pyrimidin-3-yl)acetamide
Pyrazoles
Pyrimidines
Radiopharmaceuticals
Receptors, GABA-A
Tspo protein, rat