A cholecystokinin B receptor antagonist and cocaine interaction, phase I study.

AIMS: RPR 102681, a cholecystokinin-B antagonist, increased dopamine (DA) release and reduced cocaine self-administration in animals. This pilot study sought to assess the safety and pharmacokinetics (PK) of co-administration of RPR 102681 and cocaine, and to confirm the DA release mechanism of RPR 102681. METHODS: Sixteen cocaine-dependent participants were randomized to either placebo or RPR102681 at 3 ascending doses; cocaine was co-administered at steady state of RPR 102681. [11 C]raclopride positron emission tomography scans were conducted at baseline and at each RPR102681 dose. RESULTS: RPR 102681 was well tolerated, and safe to co-administer with cocaine. RPR 102681 did not alter the PK of either cocaine or its metabolite benzoylecgonine and showed no intrinsic abuse liability. There was a trend toward reduction of cocaine craving scores. In contrast to animal studies, RPR 102681 significantly increased the binding potential of [11 C]raclopride in the ventral striatum (t test, P < .001) and caudate nucleus (t test, P < .0001) in a small subset of patients, suggesting that it may reduce intrasynaptic striatal DA. CONCLUSION: Overall, this pilot study suggests that RPR 102681 would be unlikely candidate, as an agonist medication for the treatment for cocaine addiction but worth investigating further for possible role in reducing craving.

Positron emission tomography experience with 2-[¹8F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[¹8F]FA) in the living human brain of smokers with paranoid schizophrenia.

Utilizing postmortem data (Breese et al. [2000] Neuropsychopharmacology 23:351-364), we hypothesized that the densities of high-affinity neuronal α4ß2 nicotinic acetylcholine receptors (nAChRs) in the brain exist in a continuum from highest to lowest as follows: smokers without schizophrenia > smokers with schizophrenia > nonsmokers without schizophrenia > nonsmokers with schizophrenia. Application of the Kruskal-Wallis Test (Statacorp, 2003) to the postmortem data (Breese et al. [2000] Neuropsychopharmacology 23:351-364) confirmed the hypothesized order in the cortex and the hippocampus and attained significance in the caudate and the thalamus. Positron emission tomography (PET) was performed for 60 min at 6 h after the intravenous administration of 444 megabequerels [MBq] (12 mCi) 2-[¹8F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[¹8F]FA), a radiotracer for high-affinity neuronal α4ß2 nAChRs, as a bolus plus continuous infusion to 10 adults (seven men and three women) (six smokers including five with paranoid schizophrenia and four nonsmokers) ranging in age from 22 to 56 years (mean 40.1, standard deviation 13.6). The thalamic nondisplaceable binding potential (BP(ND) ) was 1.32 ± 0.19 (mean ± standard deviation) for healthy control nonsmokers; 0.50 ± 0.19 for smokers with paranoid schizophrenia; and 0.51 for the single smoker without paranoid schizophrenia. The thalamic BP(ND) s of nonsmokers were significantly higher than those of smokers who smoked cigarettes a few hours before the scans (P = 0.0105) (StataCorp, 2003), which was likely due to occupancy of nAChRs by inhaled nicotine in smokers. Further research is needed to rule out the effects of confounding variables.

Single photon emission computed tomography experience with (S)-5-[(123)I]iodo-3-(2-azetidinylmethoxy)pyridine in the living human brain of smokers and nonsmokers.

(S)-5-[(123)I]iodo-3-(2-azetidinylmethoxy)pyridine (5-[(123)I]IA), a novel potent radioligand for high-affinity alpha4beta2* neuronal nicotinic acetylcholine receptors (nAChRs), provides a means to evaluate the density and the distribution of nAChRs in the living human brain. We sought in healthy adult smokers and nonsmokers to (1) evaluate the safety, tolerability, and efficacy of 5-[(123)I]IA in an open nonblind trial and (2) to estimate the density and the distribution of alpha(4)beta(2)* nAChRs in the brain. Single photon emission computed tomography (SPECT) was performed for 5 h after the i.v. administration of approximately 0.001 microg/kg ( approximately 10 mCi) 5-[(123)I]IA. Blood pressure, heart rate, and neurobehavioral status were monitored before, during, and after the administration of 5-[(123)I]IA to 12 healthy adults (8 men and 4 women) (6 smokers and 6 nonsmokers) ranging in age from 19 to 46 years (mean = 28.25, standard deviation = 8.20). High plasma-nicotine level was significantly associated with low 5-[(123)I]IA binding in: (1) the caudate head, the cerebellum, the cortex, and the putamen, utilizing both the Sign and Mann-Whitney U-tests; (2) the fusiform gyrus, the hippocampus, the parahippocampus, and the pons utilizing the Mann-Whitney U-test; and (3) the thalamus utilizing the Sign test. We conclude that 5-[(123)I]IA is a safe, well-tolerated, and effective pharmacologic agent for human subjects to estimate high-affinity alpha4/beta2 nAChRs in the living human brain.

A consistent and efficient graphical analysis method to improve the quantification of reversible tracer binding in radioligand receptor dynamic PET studies.

The widely used Logan plot in radioligand receptor dynamic PET studies produces marked noise-induced negative biases in the estimates of total distribution volume (DV(T)) and binding potential (BP). To avoid the inconsistencies in the estimates from the Logan plot, a new graphical analysis method was proposed and characterized in this study. The new plot with plasma input and with reference tissue input was first derived to estimate DV(T) and BP. A condition was provided to ensure that the estimate from the new plot equals DV(T) or BP. It was demonstrated theoretically that 1) the statistical expectations of the estimates from the new plot with given input are independent of the noise of the target tissue concentration measured by PET; and 2) the estimates from the time activity curves of regions of interest are identical to those from the parametric images for the new plot. The theoretical results of the new plot were also confirmed by computer simulations and fifty-five human [(11)C]raclopride dynamic PET studies. By contrast, the marked noise-induced underestimation in the DV(T) and BP images and noise-induced negative bias in the estimates from the Logan plot were demonstrated by the same data sets used for the new plot. The computational time for generating DV(T) or BP images in the human studies was reduced by 80% on average by the new plot in contrast to the Logan plot. In conclusion, the new plot is a consistent and computationally efficient graphical analysis method to improve the quantification of reversible tracer binding in radioligand receptor dynamic PET studies.

An extended simplified reference tissue model for the quantification of dynamic PET with amphetamine challenge.

BACKGROUND: Equilibrium analysis to quantify dynamic positron emission tomography (PET) with bolus followed by continuous tracer infusion and acute amphetamine challenge assumes that all tissue kinetics attain steady states during pre- and post-challenge phases. Violations of this assumption may result in unreliable estimation of the amphetamine-induced percent change in the binding potential (DeltaBP%). METHOD: We derived an extended simplified reference tissue model (ESRTM) for modeling tracer kinetics in the pre- and post-challenge phases. Ninety-minute [11C]raclopride PET studies with bolus injection followed by continuous tracer infusion were performed on 18 monkeys and 2 baboons. Forty minutes after the bolus injection, a single acute intravenous amphetamine administration was given of 2.0 mg/kg to monkeys and of 0.05, 0.1, 0.5, and 1.5 mg/kg to baboons. Computer simulations further evaluated and characterized the ESRTM. RESULTS: In monkey studies, the DeltaBP% estimated by the ESRTM was 32+/-11, whereas, the DeltaBP% obtained using the equilibrium methods was 32% to 81% lower. In baboon studies, the DeltaBP% values estimated with the ESRTM showed a linear relationship between the DeltaBP% and the natural logarithm of amphetamine dose (R2=0.96), where the DeltaBP%=10.67Ln(dose)+33.79 (0.05