Indium-Labeled Macrocyclic Conjugates of Naltrindole: High-Affinity Radioligands for In Vivo Studies of Peripheral δ Opioid Receptors

Abstract

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 delta 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 delta sites in vitro. The [111In]-labeled complexes can be prepared in good isolated yields ( approximately 65%) with high specific radioactivities (>3300 mCi/mumol). The spacers serve as pharmacokinetic modifiers, and log D7.4 values range from -2.74 to -1.79. These radioligands exhibit a high level of specific binding (75-94%) to delta 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.