2026-05-26T05:06:46Z https://rodare.hzdr.de/oai2d

oai:rodare.hzdr.de:1381 2022-08-10T12:38:36Z openaire_data user-health user-rodare

true 3.1 HZDR.RODARE 10.14278/rodare.1381 Moldovan, Rares-Petru 0000-0003-3119-7945 HZDR Gündel, Daniel 0000-0001-9743-2325 HZDR Deuther-Conrad, Winnie 0000-0003-3168-3062 HZDR Ueberham, Lea Kaur, Sarandeep HZDR Otikova, Elina Teodoro, Rodrigo 0000-0002-1425-0567 HZDR Lai, Thu Hang 0000-0001-8157-8979 HZDR Clauß, Oliver 0000-0001-5067-4845 HZDR Scheunemann, Matthias HZDR Bormans, Guy Kopka, Klaus 0000-0003-4846-1271 HZDR Bachmann, Michael 0000-0002-8029-5755 HZDR Brust, Peter 0000-0001-5555-7058 HZDR Rodare 2022 cannabinoid receptor type 2 naphthyrid-2-one binding affinity 2022-08-09 https://rodare.hzdr.de/record/1381 https://www.hzdr.de/publications/Publ-34030 https://www.hzdr.de/publications/Publ-33987 10.14278/rodare.1380 https://rodare.hzdr.de/communities/health https://rodare.hzdr.de/communities/rodare Creative Commons Attribution 4.0 International Open Access <p>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.</p>