Quantification of delta-opioid receptors in human brain with N1'-([11C]methyl) naltrindole and positron emission tomography.

The regional binding of N1'-([11C]methyl)naltrindole (MeNTI), a selective delta-opioid antagonist, was studied in healthy human subjects with positron emission tomography (PET). After the bolus intravenous administration of high specific activity [11C]MeNTI, PET was performed over 90 minutes. Arterial plasma samples were obtained during the scanning period and assayed for the presence of radiolabeled metabolites. The data were analyzed with various kinetic (two- and three-compartment models, Patlak graphical analysis) and nonkinetic (apparent volume of distribution and activity at a late scanning time) approaches. This tracer showed irreversible binding characteristics during the scanning period used. The results of the analyses also were compared with the density and distribution of delta-opioid receptors in the human brain in vitro. Additionally, computer simulations were performed to assess the effects of changes in receptor binding and tracer transport changes on the perceived binding parameters obtained with the models. A constrained three-compartment kinetic model was demonstrated to be superior to other quantification models for the description of MeNTI kinetics and quantification of delta receptor binding in the human brain with 11C-labeled MeNTI.

Imaging of delta- and mu-opioid receptors in temporal lobe epilepsy by positron emission tomography.

The involvement of opioid neurotransmitter systems in seizure mechanisms is well documented. In previous positron emission tomography (PET) studies in patients with unilateral temporal lobe epilepsy, we have found evidence for differential regulation of the opioid-receptor subtypes. The present study extends our previous observations to delta-opioid receptors by using the delta-receptor-selective antagonist [11C]methylnaltrindole ([11C]MeNTI). Paired measurements of delta- and mu-opioid receptor binding and metabolic activity were performed with PET using [11C]MeNTI and [11C]carfentanil ([11C]CFN) and [18F]fluorodeoxyglucose ([18F]FDG), respectively. Binding of [11C]MeNTI and [11C]CFN increased and [18F]FDG uptake decreased in the temporal cortex (TC) ipsilateral to the focus. Decreases in [18F]FDG uptake were more widespread regionally than were increases in opioid receptors. Increases in the delta- and mu-receptor binding showed different regional patterns. Increases in mu-receptor binding were confined to the middle aspect of the inferior TC, whereas binding of delta receptors increased in the mid-inferior TC and anterior aspect of the middle and superior TC. The increase in delta receptors suggests their anticonvulsant action, as previously shown for the delta-receptor subtype, whereas the different regional pattern of receptor alterations suggest the distinct roles of different opioid-receptor subtypes in seizure phenomena.

Imaging of delta opioid receptors in human brain by N1'-([11C]methyl)naltrindole and PET.

Recently, we have developed the positron emitting radiotracer N1'-([11C]methyl)naltrindole ([11C]MeNTI) and demonstrated its high selectivity for delta opioid receptors in the mouse brain [Lever et al. (1992) Eur. J. Pharmacol., 216:449-450]. In the present study, we examined the selectivity of [11C]MeNTI for the delta opioid receptor in the human brain, using positron emission tomography (PET). The regional kinetics and distribution as well as the pharmacology confirmed the selectivity of [11C]MeNTI for delta opioid receptor in the human brain. First, the regional kinetics of [11C]MeNTI are in accordance with the density of the delta opioid receptor. Rapid washout in receptor-poor areas and prolonged retention in receptor-rich areas were observed. Second, the regional distribution of [11C]MeNTI correlated well (r = 0.91) with the in vitro distribution of delta opioid sites but not with mu or kappa site densities (r < or = 0.008 or r < or = 0.014, respectively). [11C]MeNTI binding was highest in regions of the neocortex (insular, parietal, frontal, cingulate, and occipital), caudate nucleus, and putamen. Binding was intermediate in the amygdala and lowest in the cerebellum and thalamus. Third, studies using the competitive antagonist naltrexone demonstrated the inhibition of [11C]MeNTI binding. Naltrexone inhibition of [11C]MeNTI binding was most effective in delta receptor-rich regions, and its inhibitory potency correlated well (r = 0.88) with the regional distribution of delta opioid sites. [11C]MeNTI is the first radioligand which selectively labels delta opioid receptors in vivo in the human brain following systemic administration. The availability of [11C]MeNTI will enable a receptor specific analysis of the role of [11C]MeNTI receptors in normal and abnormal human brain.

In vivo labeling of delta opioid receptors in mouse brain by [3H]benzylidenenaltrexone, a ligand selective for the delta 1 subtype.

(E)-7-Benzylidenenaltrexone (BNTX) is a selective ligand for the putative delta 1 (delta 1) opioid receptor. To explore the feasibility of labeling delta 1 sites in vivo; we determined the cerebral distribution of radioactivity after systemic administration of [3H]BNTX to CD1 mice. Uptake was highest in striatum and lowest in cerebellum throughout the 4 hr time course. Specific radioligand binding, approximated as the difference in radioactivity concentrations between striatum and cerebellum, peaked at 0.32 percent injected dose/g at 30 min and comprised a modest 23% of total striatal radioactivity. For seven brain regions, radioactivity concentrations correlated with delta site densities known from prior in vitro studies (rS = 0.79, p = 0.03), and also with the uptake of N1'-([11C]methyl)naltrindole in vivo (rS = 0.78, p = 0.04) in mice. Specific binding in striatum, olfactory tubercles and cortical regions was saturable by BNTX, and was inhibited stereoselectively by the optical isomers of naloxone. Naltrindole and naltriben (NTB), delta antagonists, blocked 65-99% of [3H]BNTX specific binding at a dosage of 5.0 mumol/kg. Similar doses of the mu antagonist cyprodime, or the kappa agonist U50,488H, did not inhibit binding. Adjusted for the four-fold greater brain penetration of NTB relative to BNTX, dose-response studies suggested that delta 1 selective BNTX (ED50 = 1.51 mumol/kg) was 50% more potent than delta 2 selective NTB (ED50 = 0.56 mumol/kg) in blocking specific [3H]BNTX binding in striatum. In CXBK mice, a strain with functional delta 1 but not delta 2 receptors in antinociceptive assays, radioligand uptake and distribution proved similar to that in CD1 mice. In sum, [3H]BNTX labels murine delta opioid receptors in vivo with a low extent of specific binding. The data is consistent with, but not conclusive for, selective labeling of the delta 1 subtype.

Synthesis of radioiodinated naltrindole analogues: ligands for studies of delta opioid receptors.

Analogues of naltrindole and N1'-methylnaltrindole having radioiodine in the 7'-position of the indole ring have been prepared for evaluation as delta opioid receptor ligands. The no-carrier-added radiosyntheses were conducted by Cu(I) assisted nucleophilic exchange of radioiodide for bromide under reducing conditions at 190 degrees C. A combination of HPLC and solid-phase extraction gave the 125I- or 123I-labeled products in satisfactory yields (47%) with high radiochemical purities (> 98%) and high specific activities (125I: 43-68 GBq/mumol, 1155-1833 mCi/mumol; 123I: > 92 GBq/mumol, 2500 mCi/mumol).

In vivo binding of N1'-([11C]methyl)naltrindole to delta-opioid receptors in mouse brain.

The regional distribution of N1'-([11C]methyl)naltrindole ([11C]MeNTI) in vivo in mouse brain correlates with established delta opioid receptor densities in vitro. [11C]MeNTI binding is blocked by naltrindole, a delta antagonist, but not by cyprodime, a mu antagonist, of by (+/-)-U50,488, a kappa agonist. Thus, [11C]MeNTI selectively labels central delta opioid receptors in vivo in mouse, and shows promise for positron emission tomography studies of delta sites in human brain.