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

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 (KD = 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.