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

Abstract

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--Lys(Z)-OH (reference compound 1) is a useful starting point for the synthesis of (18)F-labeled compounds prepared by the coupling of N-succinimidyl 4-[ (18)F]fluorobenzoate ([(18)F]SFB) with Boc-Dmt-Tic--Lys(Z)-OH under 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 [(18)F]- 1 was about 25-30% ( n = 5) starting from [(18)F]SFB ( n = 5) with an effective specific activity about 46 GBq/micromol. In vitro autoradiography studies showed prominent uptake of [ (18)F]- 1 in the striatum and cortex with significant blocking by 1 and UFP-501 (selective delta-opioid receptor antagonist), suggesting high specific binding of [(18)F]- 1 to delta-opioid receptors. Noninvasive microPET imaging studies revealed the absence of [(18)F]- 1 in rat brain, since it fails to cross the blood-brain barrier. This study demonstrates the suitability of [ (18)F]- 1 for imaging peripheral delta-opioid receptors.

Figure 1

Radioautography of rat brain slices incubated with [¹⁸F]-1. In vitro autoradiograms of coronal sections from rat brain in the presence of (A) [¹⁸F]-1, (B) [¹⁸F]-1 and 1 (10 µM), and (C) [¹⁸F]-1 and UPF-501 (10 µM).

Figure. 2

In vivo PET analysis of the distribution of [¹⁸F]-1 in rats. Representative coronal, transaxial, and sagittal microPET images of [¹⁸F]-1 in the normal Sprague-Dawley rat brain 15 min after femoral vein injection as detailed in the Experimental Section.

Scheme 1

Synthesis of compound 1.

Scheme 2

Synthesis of compound 2.

Scheme 3

Synthesis of [¹⁸F]-1.