Assessment of a 6-arylaminobenzamide lead derivative as a potential core scaffold for S1P₅ positron emission...

Sphingosine-1-phosphate-5 receptors (S1P₅) are predominantly expressed in oligodendrocytes and as a result have been proposed as an important target in Multiple Sclerosis (MS). Selective S1P₅ radiotracers could enable in vivo positron emission tomography (PET) imaging of oligodendrocytes activity. Here we report the synthesis, radiolabelling and first preclinical evaluation of the pharmacokinetics and binding properties of a lead 6-arylaminobenzamide derivative, 6-(mesitylamino)-2-methoxy-3-methylbenzamide (also named as TEFM180), as a potential core scaffold for development of novel S1P₅ PET radiotracers. Following intravenous bolus injection, TEFM180 was found to quickly enter the brain with good brain:blood ratios and subsequent rapid clearance. Autoradiography studies showed that [³H]TEFM180 had a high affinity for its target (K_D = 2.8 nM), with moderate levels of non-displaceable binding. Distribution of [³H]TEFM180 in the brain was found to be consistent with S1P₅ expression and showed a binding potential (BP) of >2-3 in white matter rich regions. Overall, TEFM180 offers a good initial platform for development of future radiotracers targeting S1P₅.