Dataset Open Access

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

Moldovan, Rares-Petru; Gündel, Daniel; Deuther-Conrad, Winnie; Ueberham, Lea; Kaur, Sarandeep; Otikova, Elina; Teodoro, Rodrigo; Lai, Thu Hang; Clauß, Oliver; Scheunemann, Matthias; Bormans, Guy; Kopka, Klaus; Bachmann, Michael; Brust, Peter


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    <subfield code="a">&lt;p&gt;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 (&lt;strong&gt;[&lt;sup&gt;18&lt;/sup&gt;F]5&lt;/strong&gt;). In this study we aimed at the development of a novel &lt;sup&gt;18&lt;/sup&gt;F-labeled CB2R radioligand with improved binding properties and metabolic stability. Starting from the structure of &lt;strong&gt;5&lt;/strong&gt;, we developed a novel series of fluorinated derivatives by modifying the substituents at the naphthyrid-2-one subunit. Compound &lt;strong&gt;28&lt;/strong&gt; (&lt;strong&gt;LU13&lt;/strong&gt;) was identified with the highest binding affinity and selectivity versus CB1R (CB2R&lt;em&gt;K&lt;/em&gt;&lt;sub&gt;i&lt;/sub&gt; = 0.6 nM; CB1R&lt;em&gt;K&lt;/em&gt;&lt;sub&gt;i&lt;/sub&gt;/CB2R&lt;em&gt;K&lt;/em&gt;&lt;sub&gt;i&lt;/sub&gt; &amp;gt; 1000) and was selected for radiolabeling with &lt;sup&gt;18&lt;/sup&gt;F and biological characterization. The radiofluorination was performed starting from the corresponding bromo-precursor (&lt;strong&gt;31&lt;/strong&gt;) bearing a fully deuterated &lt;em&gt;N&lt;/em&gt;-alkyl chain to protect against defluorination. The in vitro evaluation of &lt;strong&gt;[&lt;sup&gt;18&lt;/sup&gt;F]LU13 &lt;/strong&gt;proved the high binding affinity of the radioligand towards rat (rCB2R&lt;em&gt;K&lt;/em&gt;&lt;sub&gt;D&lt;/sub&gt; = 0.2 nM) and human (hCB2R&lt;em&gt;K&lt;/em&gt;&lt;sub&gt;D&lt;/sub&gt; = 1.1 nM) CB2R. Metabolism studies in mice revealed a metabolic stability at 30 min p.i. with fractions of parent compound of &amp;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 &lt;strong&gt;[&lt;sup&gt;18&lt;/sup&gt;F]LU13&lt;/strong&gt; to reach and selectively label the hCB2R in the brain. Thus, &lt;strong&gt;[&lt;sup&gt;18&lt;/sup&gt;F]LU13 &lt;/strong&gt;is a novel and highly promising PET radioligand for the imaging of up regulated CB2R expression under pathological conditions in the brain.&lt;/p&gt;</subfield>
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