TY - JOUR A1 - Moldovan, R.-P. A1 - Wenzel, B. A1 - Teodoro, R. A1 - Neumann, W. A1 - Dukic-Stefanovic, S. A1 - Kraus, Werner A1 - Rong, P. A1 - Deuther-Conrad, W. A1 - Hey-Hawkins, E. A1 - Krügel, U. A1 - Brust, P. T1 - Studies towards the development of a PET radiotracer for imaging of the P2Y1 receptors in the brain: synthesis, 18F-labeling and preliminary biological evaluation JF - European Journal of Medicinal Chemistry N2 - Purine nucleotides such as ATP and ADP are important extracellular signaling molecules in almost all tissues activating various subtypes of purinoreceptors. In the brain, the P2Y1 receptor (P2Y1R) subtype mediates trophic functions like differentiation and proliferation, and modulates fast synaptic transmission, both suggested to be affected in diseases of the central nervous system. Research on P2Y1R is limited because suitable brain-penetrating P2Y1R-selective tracers are not yet available. Here, we describe the first efforts to develop an 18F-labeled PET tracer based on the structure of the highly affine and selective, non-nucleotidic P2Y1R allosteric modulator 1-(2-[2-(tert-butyl)phenoxy]pyridin-3-yl)-3- [4-(trifluoromethoxy)phenyl]urea (7). A small series of fluorinated compounds was developed by systematic modification of the p-(trifluoromethoxy)phenyl, the urea and the 2-pyridyl subunits of the lead compound 7. Additionally, the p-(trifluoromethoxy)phenyl subunit was substituted by carborane, a boron-rich cluster with potential applicability in boron neutron capture therapy (BNCT). By functional assays, the new fluorinated derivative 1-{2-[2-(tert-butyl)phenoxy]pyridin-3-yl}-3-[4-(2-fluoroethyl) phenyl]urea (18) was identified with a high P2Y1R antagonistic potency (IC50 ¼10 nM). Compound [18F] 18 was radiosynthesized by using tetra-n-butyl ammonium [18F]fluoride with high radiochemical purity, radiochemical yield and molar activities. Investigation of brain homogenates using hydrophilic interaction chromatography (HILIC) revealed [18F]fluoride as major radiometabolite. Although [18F]18 showed fast in vivo metabolization, the high potency and unique allosteric binding mode makes this class of compounds interesting for further optimizations and investigation of the theranostic potential as PET tracer and BNCT agent. KW - Purine P2Y1 receptors KW - Positron emission tomography KW - Brain PET tracers KW - Radiometabolites KW - Micellar chromatography KW - Hydrophilic interaction chromatography PY - 2019 DO - https://doi.org/10.1016/j.ejmech.2019.01.006 SN - 0223-5234 VL - 165 SP - 142 EP - 159 PB - Elsevier CY - Amsterdam AN - OPUS4-47253 LA - eng AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER -