Our goal is to design, synthesize and evaluate H-3 and I-125 labeled radioligands for basic science studies of cerebral delta opioid receptors in vivo and in vitro. We shall place particular emphasis upon identification of radioligands 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, these radioligands are not suitable for in vivo studies because of poor brain penetration. Recently, we prepared an analog of the potent, non-peptide delta opioid receptor antagonist naltrindole (NTI) radiolabeled with C-11, a positron emitting radionuclide. This compound, N1'-([11C]- methyl)naltrindole ([11C]-MeNTI), is the first radioligand which allows selective localization of central delta opioid receptors in vivo. [11C]- MeNTI shows promise for positron emission tomography (PET) studies of delta sites in human brain based upon a clinical trial in fully informed volunteers under the auspices of prior Institutional and Federal approvals. NTI proper has been labeled with H-3, and shown to be a useful, high affinity (Kd delta = 0.037 nM) radioligand for in vitro studies by others. As a consequence of the great interest in delta opioid receptors, [3H]-NTI has just become commercially available. However, we have found that [3H]-NTI is not suitable for in vivo studies. Thus, we propose to prepare and validate [3H]-MeNTI for basic in vivo work in small animals. Further, we propose to investigate a series of NTI analogs, including the benzofuran congener, labeled with either H-3 or I-125 in order to identify optimal radioligands for such in vivo studies. We have already prepared I- 125 labeled 7'-iodonaltrindole ([125I]-INTI), and have found that this radioligand allows selective labeling of central delta opioid receptors in vivo in mice. Further, we propose to establish qualitative structure activity relationships between lipophilicity and in vitro affinity, as well as in vivo uptake, retention and tissue contrast for this important class of compounds. Finally, we propose an exploratory investigation of radioligands for selective localization of the delta1 opioid -receptor subtype. Initially, this involves preparation of a H-3 labeled version of 7-benzylidenenaltrexone, developed by Portoghese et al. as the first delta1 selective ligand. The delta opioid receptor is implicated in neuropsychiatric, neurodegenerative and seizure disorders, and plays a particularly prominent role in the neurobiology of substance abuse. Therapeutic delta antagonists are of much interest for pharmacotherapy of cocaine abuse, and for attenuation of the untoward effects of mu agonists without concomitant reduction of antinociception. Identification of optimal radioligands to selectively localize delta sites in vivo would have substantial positive impact upon hypothesis driven, basic science studies of delta opioid receptor function, and could facilitate new drug discovery efforts directed toward therapeutic delta antagonists.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Public Health & Prev Medicine
Schools of Public Health
United States
Zip Code