Structure-Based Design, Optimization, and Development of [¹⁸F]LU13: A Novel Radioligand for Cannabinoid Receptor Type 2 Imaging in the Brain with PET

Abstract

The cannabinoid receptor type 2 (CB2R) is an attractive target for the diagnosis and therapy of neurodegenerative diseases and cancer. In this study, we aimed at the development of a novel ¹⁸F-labeled radioligand starting from the structure of the known naphthyrid-2-one CB2R ligands. Compound <b>28</b> (<b>LU13</b>) was identified with the highest binding affinity and selectivity versus CB1R (CB2R<i>K</i>_i = 0.6 nM; CB1R<i>K</i>_i/CB2R<i>K</i>_i > 1000) and was selected for radiolabeling with fluorine-18 and biological characterization. The new radioligand <b>[</b>^<b>18</b><b>F]LU13</b> showed high CB2R affinity in vitro as well as high metabolic stability in vivo. PET imaging with <b>[</b>^<b>18</b><b>F]LU13</b> in a rat model of vector-based/-related hCB2R overexpression in the striatum revealed a high signal-to-background ratio. Thus, <b>[</b>^<b>18</b><b>F]LU13</b> is a novel and highly promising PET radioligand for the imaging of upregulated CB2R expression under pathological conditions in the brain.