Indium-labeled macrocyclic conjugates of naltrindole: High-affinity radioligands for in vivo studies of peripheral δ opioid receptors

We have identified a series of hydrophilic indium-labeled DOTA and DO3A conjugates of naltrindole (NTI) that are suited to in vivo studies of peripheral δ opioid receptors. Indium(III) complexes, linked to the indole nitrogen of NTI by six- to nine-atom spacers, display high affinities (0,1-0,2 nM) and excellent selectivities for binding to δ sites in vitro. The [ ¹¹¹In]-labeled complexes can be prepared in good isolated yields (∼65%) with high specific radioactivities (>3300 mCi/μmol), The spacers serve as pharmacokinetic modifiers, and log D_7.4 values range from -2,74 to -1,79, These radioligands exhibit a high level of specific binding (75-94%) to δ opioid receptors in mouse gut, heart, spleen, and pancreas in vivo. Uptakes of radioactivity are saturable by the non-radioactive complexes, inhibited by naltrexone, and blocked by NTI. Thus, these radiometal-labeled NTI analogues warrant further study by single-photon emission computed tomography.