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Inhalant abuse is a rapidly growing health problem particularly among adolescents. Yet we know little about the neural mechanisms underlying the abuse liability of inhalants, particularly when compared to other addictive drugs. Specifically, our understanding of the relationship between the regional brain pharmacokinetics and features classically associated with drug reinforcement is lacking. Under the hypothesis that the abuse liability of toluene can be related to its pharmacokinetic properties and the pattern of regional brain uptake, we developed the methodology for radiolabeling and purifying [11C]toluene for use in PET studies. Here we report the regional brain distribution and kinetics of the widely abused solvent toluene in non-human primates and the whole body biodistribution in mice.To our knowledge, this is the first reported study of the in vivo brain pharmacokinetics of labeled toluene in non-human primates. Rapid uptake of radioactivity into striatal and frontal regions was followed by rapid clearance from the brain. Concurrent findings in rodents indicate similar radiotracer kinetics, with excretion through kidneys and liver. Taken together, our data provides insight into pharmacokinetic features possibly associated with the abuse liability of toluene. [Copyright &y& Elsevier]

This study evaluates the effects of age on DA D2 receptors in extrastriatal regions. DA D2 receptor availability was evaluated in 42 healthy male subjects (mean age 41 +/- 16, range 21 - 86 year old) with positron emission tomography (PET) and [11C]raclopride. Estimates of Bmax/Kd were obtained using the ratio of the distribution volume in the region of interest (caudate, putamen, thalamus, frontal, occipital cortices, temporal insula, cingulate and orbitofrontal gyri) to that in cerebellum. Correlations between age and D2 receptors were significant in putamen (r = -0.58, p < or = 0.0001), caudate (r = -0.54, p < or = 0.0002), thalamus (r = -0.33, p < or = 0.03) and temporal insula (r = -0.39, p < or = 0.01) but not in any of the frontal regions. The decrease in DA D2 receptor availability was 6.6% per decade in caudate, 8.2% in putamen, 7.6% in thalamus and 13% in temporal insula. This study indicates that D2 losses with age are not limited to striatum and involve also thalamic as well as temporal cortical regions.

Ro41-0960 is a potent, fluorine containing COMT inhibitor which has be en reported to cross the blood brain barrier and to inhibit COMT in the brain. It is structurally similar to Ro40-7592 which is currently undergoing clinical trials in Parkinson's disease. Positron emission tomographic (PET) studies in baboon using F-18 labeled Ro41-0960 demonstrated a negligible uptake in the brain both at tracer doses and with the addition of unlabeled drug (1.5 mg/kg) at all times through a 90 min experimental interval. The brain to plasma ratios of F-18 averaged about 0.025. Region of interest analysis of the brain tissue area suggests that most of F-18 in the brain was due to the blood in the brain and not the brain tissue itself. However, high uptake was observed in the kidneys and in other organs which are known to have high COMT activity. Studies in mice showed that at 30 min after injection of tracer, F-18 in kidneys was largely as unchanged [18F]Ro41-0960 and that it could be displaced with unlabeled Ro41-0960. The fact that the average brain to blood ratio for mice (n=12) was 0.04, and that similar HPLC metabolite patterns were observed for brain and blood, provides consistent evidence that nearly all the F-18 in the brain represents F-18 in the cerebral blood vessels. These studies raise the question of whether the central pharmacological effects of Ro41-0960 are due to its presence in the brain. They also provide the first example of a positron emitter labeled radiotracer for COMT, and provide initial encouraging evidence that [18F]Ro41-0960 may be used to examine COMT in peripheral organs in vivo.

We compared the sensitivity of two dopamine transporter (DAT) ligands ([C-11]cocaine and [C-11]d-threo-methylphenidate) for measurement of extrastriatal DAT availability using positron emission tomography (PET) on separated groups of 10 age matched male volunteers (age range, 21-49 years). DAT availability was obtained using the ratio of the distribution volume in the region of interest to that in the cerebellum (Bmax'/Kd'+ 1). DAT availability measured with [C-11]d-threo-methylphenidate was highest in basal ganglia, followed by thalamus > temporal insula, cingulate > orbitofrontal, frontal and occipital cortices. A similar ranking order for DAT availability was obtained with [C-11]cocaine. Specific binding (Bmax'/Kd') of [C-11]cocaine in thalamus was 25-33% that of basal ganglia and [C-11]d-threo-methylphenidate in thalamus was 11-13% that of basal ganglia. The regional measures with [C-11]cocaine were significantly correlated with those of [C-11]d-threo-methylphenidate (p < or = 0.0001). These results document extrastriatal binding in human brain with two different DAT ligands.

Increases in kidney size and function are characteristic features of the early stages of Type I diabetes mellitus, and may contribute to the pathogenesis of diabetic nephropathy. Other studies have shown that the relative circulating concentrations of insulin and glucagon may be regulatory to renal growth and function. In order to elucidate the role of pancreatic glucagon in diabetic renal growth, subtotal pancreatectomy was performed prior to administration of streptozotocin to rats. Glycosuria and kidney weight were significantly reduced by subtotal pancreatectomy, although creatinine clearance and blood glucose levels were not different from diabetic controls. These data suggest that hyperglucagonemia may be an important mediator of renal growth in insulinopenic diabetes mellitus.