Synthesis of a potent and selective F-18-Labeled delta-opioid receptor antagonist derived from the Dmt-Tic pharmacophore for positron emission tomography imaging

摘要

Identification and pharmacological characterization of two new selective delta-opioid receptor antagonists, derived from the Dmt-Tic pharmacophore, of potential utility in positron emission tomography (PET) imaging are described. On the basis of its high delta selectivity, H-Dmt-Tic-epsilon-Lys(Z)-OH (reference compound 1) is a useful starting point for the synthesis of F-18-labeled compounds prepared by the coupling of N-succinimidyl 4-[F-18]fluorobenzoate ([F-18]SFB) with Boc-Dmt-Tic-epsilon-Lys(Z)-OH tinder slightly basic conditions at 37 degrees C for 15 min, deprotection with TFA, and HPLC purification. The total synthesis time was 120 min, and the decay-corrected radiochemical yield of [F-18]-1 was about 25-30% (n = 5) starting from [F-18]SFB (n = 5) with an effective specific activity about 46 GBq/mu mol. In vitro autoradiography studies showed prominent uptake of [F-18]-1 in the striatum and cortex with significant blocking by 1 and UFP-501 (selective d-opioid receptor antagonist), suggesting high specific binding of [F-18]-1 to delta-opioid receptors. Noninvasive microPET imaging studies revealed the absence of [18F]-1 in rat brain, since it fails to cross the blood-brain barrier. This study demonstrates the suitability of [F-18]-1 for imaging peripheral delta-opioid receptors.