Our goal is to design, synthesize and evaluate H-3 and I-125 labeled radiogands for basic science studies of cerebral delta (delta) opoid receptors in vivo and in vitro. We shall place particular emphasis upon identification of radioglands which are optimal for in vivo studies of (delta) sites in animal (rodent) models. Although peptides radiolabeled with H-3 or I-125 are available for in vitro studies of (delta) receptors, they arenot well-suited to in vivo studes because of poor brain penetration. Recently, we prepared, we prepared NI'-([11C]- menthyl) naltrindole ([11C]-MeNTI), the first radioligand which allows localization of central (delta) opioid receptors in vivo. It is used at Johns Hopkin for PET studies in fully informed volunteers and selected patients. We have synthesize several N1'-alkyl and 7'-halo substituted NTI analogs, and defined their binding profile at (mu) kappa1 and delta sites in membranes from brain homogenates. All display high primary apparent affinity for (delta) sites, with an approximately 100-to 300- fold weaker secondary binding interaction to kappa1 sites. Selectively for (delta) over (mu) sites ranged from 100-to 1500-fold. Increasing lipophilicity reduces the potency, but not the selectivity, of NTI analogs. An excellent liniear correlation (r=0.96) was found between Ki (delta) and log P. These relationships have predictive alue when the analogs considered are structurally similar. In vivo in mouse brain, the peak striatal to cerebellar radioactivity ratios observed exhibit a prabolic relationships with log P. This is consistent with a poor brain penetration by passive transfer of hydrophilic ligands ([3H]-NTI), and a slower clearance of non-specific bidning from binding from brain tissues by more hydrophobic ligands ([125I]-I-NTI). We propose to investigate additional candidate ligands derived from naltrindole (NTI), as well as benzylidenenaltrexone (BNTX) and (+)-BW373U86. A focused, medicinal chemistry approach will steer our efforts. The in vitro and in vivo data will be correlated with physicochemical parameters to refine the structure activity relationships. The (delta) opoid receptor plays a prominent role in the neurobiology of substance abuse. Therapeurtic (delta) antagonists are of interest for pharmacotherapy of cocaine abuse, and for attenuation of the untoward effects (mu) agonists without concomitant reduction of antinociception. OPtimal radioglands to localize (delta) sites selectively in vivo would have substantial positive impact upon hypothesis driven, basic science studies of (delta) opoid receptor function, and could facilitate new drug discovery efforts directed toward therapeutic (delta) antagonists.
