Synthesis and invivo 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

摘要

Imaging agents that target adenosine type2A (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 Parkinsons 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: [I-123]MNI-420 and [F-18]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 invivo results resulted in the identification of 7-(2-(4-(4-(2-[F-18]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 ([F-18]MNI-444) and 7-(2-(4-(2-fluoro-4-[I-123]iodophenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-amine ([I-123]MNI-420) as PET and SPECT radiopharmaceuticals for mapping A(2A) receptors in brain.