Data Publication: Structure-Based Design, Optimization and Development of [18F]LU13, a novel radioligand for CB2R Imaging in the Brain with PET

The cannabinoid receptor type 2 (CB2R) is an attractive target for diagnosis and therapy of neurodegenerative diseases and cancer. Recently, we reported a novel naphthyrid-2-one based positron-emission tomography (PET) radioligand for imaging of the CB2R in the brain (<strong>[¹⁸F]5</strong>). In this study we aimed at the development of a novel ¹⁸F-labeled CB2R radioligand with improved binding properties and metabolic stability. Starting from the structure of <strong>5</strong>, we developed a novel series of fluorinated derivatives by modifying the substituents at the naphthyrid-2-one subunit. Compound <strong>28</strong> (<strong>LU13</strong>) was identified with the highest binding affinity and selectivity versus CB1R (CB2R<em>K</em>_i = 0.6 nM; CB1R<em>K</em>_i/CB2R<em>K</em>_i &gt; 1000) and was selected for radiolabeling with ¹⁸F and biological characterization. The radiofluorination was performed starting from the corresponding bromo-precursor (<strong>31</strong>) bearing a fully deuterated <em>N</em>-alkyl chain to protect against defluorination. The in vitro evaluation of <strong>[¹⁸F]LU13 </strong>proved the high binding affinity of the radioligand towards rat (rCB2R<em>K</em>_D = 0.2 nM) and human (hCB2R<em>K</em>_D = 1.1 nM) CB2R. Metabolism studies in mice revealed a metabolic stability at 30 min p.i. with fractions of parent compound of &gt;80% in the brain and 90% in the spleen with only trace of defluorination products detected in plasma. PET imaging in a rat model of vector-based/related overexpression in the striatum revealed a high signal to background ratio, demonstrating the ability of <strong>[¹⁸F]LU13</strong> to reach and selectively label the hCB2R in the brain. Thus, <strong>[¹⁸F]LU13 </strong>is a novel and highly promising PET radioligand for the imaging of up regulated CB2R expression under pathological conditions in the brain.