Our goal is to identify and validate the first radioligands for non- invasive localization and quantification of cerebral delta (delta) opioid receptors by positron emission tomography (PET) and single photon emission computed tomography (SPECT). This will have substantial positive impact upon studies of opioid receptor function in healthy people, as well as in patients suffering from neuropsychiatric, neurodegenerative and seizure disorders. The ability to assess delta sites by tomography will also aid new drug discovery efforts. This may prove particularly important since therapeutic delta antagonists have potential for the treatment of mental illness and substance abuse, as well as for attenuation of morphine tolerance and dependence without concomitant reduction of antinociceptive activity. A focused, medicinal chemistry approach will be taken in our development efforts. Specifically, analogs of the potent delta antagonist naltrindole (NTI) will be synthesized, characterized and labeled with positron emitting radionuclides (C-11, F-18) or with iodine radioisotopes (I-125, I-123). Recently, we prepared [11C]-MeNTI, and demonstrated the first selective labeling of delta opioid receptors in vivo using a mouse model (Lever et al., 1992; Appendix 1). We propose to establish delta selectively for [11C]-MeNTI by PET in baboon brain by pharmacologic interventions, and by comparison of the regional distribution with that of the selective ligand [ligand [11C]-carfentanil and the """"""""universal"""""""" ligand [11C]-diprenorphine (mu, delta, and kappa). By contrast, no radioligands for SPECT imaging of opioid receptors have been reported. We propose to establish the feasibility of such studies with the novel ligand O-([123]-iodoallyl)diprenorphine ([123]-0-IA-DPN) (Musachio and Lever, 1992; Appendix 2). To our knowledge, this is the only radioiodinated ligand that allows in vivo studies of opioid receptors. Multiple opioid receptors are labeled by [125]-O-IA-DPN in vivo in mouse brain, and [123I]-O-IA-DPN allows visualization of these sites by ex vivo autoradiography. Validation of this radioligand for SPECT will provide a new tool for opioid receptor studies, and sets the stage for development of radioiodinated naltrindole analogs selective for the delta site. The novel radioligands will be screened to define in vitro and in vivo binding profiles, physicochemical parameters, metabolism and radiation dosimetry. Promising radioligands will be tested by in vitro and ex vivo autoradiography, and by imaging trials in baboons. Our studies will provide radioligands useful for in vitro, in vivo, autoradiographic and tomographic studies of cerebral opioid receptors, and will lay the foundation for PET and SPECT studies of opioid receptors in human beings.
