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 A_2A Receptors

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• 作者：Dr. Christine Vala ; Dr. Thomas J. Morley ; Dr. Xuechun Zhang ; Dr. Caroline Papin ; Dr. Adriana Alexandre S. Tavares ; Dr. H. Sharon Lee ; Dr. Cristian Constantinescu ; Dr. Olivier Barret ; Dr. Vincent M. Carroll ; Dr. Ronald M. Baldwin ; Dr. Gilles D. Tamagnan and Dr. David Alagille
• 刊名：ChemMedChem
• 出版年：2016
• 出版时间：September 6, 2016
• 年：2016
• 卷：11
• 期：17
• 页码：1936-1943
• 全文大小：1235K
• ISSN：1860-7187

文摘

Imaging agents that target adenosine type 2A (A_2A) 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 A_2A receptor density and function in neurodegenerative diseases. We previously described the successful evaluation of two A_2A-specific radiotracers in both nonhuman primates and in subsequent human clinical trials: [¹²³I]MNI-420 and [¹⁸F]MNI-444. Herein we describe the development of both of these radiotracers by selection from a series of A_2A 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 A_2A 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-[¹⁸F]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 ([¹⁸F]MNI-444) and 7-(2-(4-(2-fluoro-4-[¹²³I]iodophenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-amine ([¹²³I]MNI-420) as PET and SPECT radiopharmaceuticals for mapping A_2A receptors in brain.