Synthesis and in vitro/in vivo pharmacological evaluation of [11C]-ThioABP, a novel radiotracer for imaging mGluR5 with PET

Abstract

We have designed a novel positron emission tomography (PET) radiotracer, [¹¹C]-ThioABP, a thiazole based derivative for imaging the metabotropic glutamate receptor subtype 5 (mGluR5), and prepared the hydroxy oxime precursor 4 in a 15% overall yield. [¹¹C]-ThioABP was radiosynthesized in the Veenstra module and obtained in a decay corrected radiochemical yield of 40% and specific activity of 80–250 GBq μmol⁻¹ at the end of synthesis. ThioABP exhibited excellent binding affinity (K_i) in vitro of 1.9 ± 0.9 nM and [¹¹C]-ThioABP showed an optimal log D_7.4 of 2.4. The autoradiographic studies on rat brain slices revealed specific binding to mGluR5. In vivo evaluation of [¹¹C]-ThioABP including a displacement study with MMPEP in a dynamic PET scan showed a specificity of [¹¹C]-ThioABP for mGluR5. Radio-TLC metabolite studies showed a good metabolic stability of [¹¹C]-ThioABP in vivo. The comparison of biological properties of [¹¹C]-ThioABP and [¹¹C]-ABP688 revealed similarity between these two compounds.