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Synthesis and in vivo Evaluation of Fluorine-18 and Iodine-123 Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine Derivatives as PET and SPECT Radiotracers for Mapping A2A Receptors.
- Source :
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ChemMedChem [ChemMedChem] 2016 Sep 06; Vol. 11 (17), pp. 1936-43. Date of Electronic Publication: 2016 Jul 13. - Publication Year :
- 2016
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Abstract
- Imaging agents that target adenosine type 2A (A2A ) receptors play an important role in evaluating new pharmaceuticals targeting these receptors, such as those currently being developed for the treatment of movement disorders like Parkinson's disease. They are also useful for monitoring progression and treatment efficacy by providing a noninvasive tool to map changes in A2A receptor density and function in neurodegenerative diseases. We previously described the successful evaluation of two A2A -specific radiotracers in both nonhuman primates and in subsequent human clinical trials: [(123) I]MNI-420 and [(18) F]MNI-444. Herein we describe the development of both of these radiotracers by selection from a series of A2A ligands, based on the pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine core of preladenant. Each of this series of 16 ligands was found to bind to recombinant human A2A receptor in the low nanomolar range, and of these 16, six were radiolabeled with either fluorine-18 or iodine-123 and evaluated in nonhuman primates. These initial in vivo results resulted in the identification of 7-(2-(4-(4-(2-[(18) F]fluoroethoxy)phenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine ([(18) F]MNI-444) and 7-(2-(4-(2-fluoro-4-[(123) I]iodophenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-amine ([(123) I]MNI-420) as PET and SPECT radiopharmaceuticals for mapping A2A receptors in brain.<br /> (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Subjects :
- Animals
Brain diagnostic imaging
Brain metabolism
Dose-Response Relationship, Drug
Female
Fluorine Radioisotopes
Heterocyclic Compounds, 3-Ring chemical synthesis
Heterocyclic Compounds, 3-Ring chemistry
Humans
Iodine Isotopes
Macaca mulatta
Molecular Conformation
Papio
Pyrimidines chemical synthesis
Pyrimidines chemistry
Radiopharmaceuticals chemical synthesis
Radiopharmaceuticals chemistry
Receptor, Adenosine A2A chemistry
Recombinant Proteins chemistry
Recombinant Proteins metabolism
Structure-Activity Relationship
Triazoles chemical synthesis
Triazoles chemistry
Heterocyclic Compounds, 3-Ring pharmacokinetics
Positron-Emission Tomography
Pyrimidines pharmacokinetics
Radioactive Tracers
Radiopharmaceuticals pharmacokinetics
Receptor, Adenosine A2A metabolism
Triazoles pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1860-7187
- Volume :
- 11
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- ChemMedChem
- Publication Type :
- Academic Journal
- Accession number :
- 27407017
- Full Text :
- https://doi.org/10.1002/cmdc.201600219