Design, synthesis and evaluation of [111In]-labeled, DOTA-conjugated tetrapeptides having high affinity and selectivity for mu opioid receptors
Abstract
Introduction Peripheral mu (μ) opioid receptors are implicated in pain, bowel dysfunction and the progression of certain cancers. In an effort to identify radioligands well suited for imaging these peripheral sites, we have prepared and evaluated four hydrophilic [111In]-labeled, DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) conjugated μ tetrapeptides. Methods Peptides were prepared by solid-phase techniques, using orthogonal strategies to achieve branching to DOTA, and then characterized by HPLC, mass spectroscopy and amino acid analysis. Scaffolds included novel peptide H-Dmt-D-Ala-Phe-Orn-NH2 (DAPO), where Dmt = 2´,6´-dimethyltyrosine, and known peptide H-Dmt-D-Arg-Phe-Lys-NH2 ([Dmt1]DALDA). Constructs had DOTA conjugation at the Orn4 or Lys4 side chains, or to the C-terminal through a hexanoic acid - lysine linker. Indium(III) complexation and [111In]-radiolabeling were accomplished by standard methods. Protein binding and Log D7.4 were determined. Binding and pharmacological profiles were obtained in vitro. Biodistribution and radiometabolite studies were conducted using male CD-1 mice. Results All four indium(III)-DOTA conjugates derived from DAPO and [Dmt1]DALDA showed good selectivity and subnanomolar affinity for μ opioid receptors. One radioligand, H-Dmt-D-Ala-Phe-Orn(δ-[111In]DOTA)-NH2, showed 25% specific binding in vivo to μ sites in mouse gut. Notably, this was the least polar of the series, and also showed low sensitivity to modulation of…
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