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Major neurochemical effects of methamphetamine include release of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) via a carrier-mediated exchange mechanism. Preclinical research supports the hypothesis that elevations of mesolimbic DA mediate the addictive and reinforcing effects of methamphetamine and amphetamine. This hypothesis has not been adequately tested in humans. Previous in vivo rodent microdialysis demonstrated that the high affinity DA uptake inhibitor, GBR12909, attenuates cocaine- and amphetamine-induced increases in mesolimbic DA. The present study determined the ability of GBR12909 to attenuate amphetamine-induced increases in striatal DA as measured by [¹¹C]raclopride continuous infusion positron emission tomography (PET) scans in two Papio anubis baboons. [¹¹C]Raclopride was given in a continuous infusion paradigm resulting in a flat volume of distribution vs. time for up to 45 min postinjection. At that time, a 1.5 mg/kg amphetamine i.v. bolus was administered which caused a significant (30.3%) reduction in the volume of distribution (V3"). The percent reduction in the volume of distribution and, hence, a measure of the intrasynaptic DA release ranged between 22–41%. GBR12909 (1 mg/kg, slow i.v. infusion) was administered 90 min before the administration of the radiotracer. The comparison of the volume of distribution before and after administration of GBR12909 showed that GBR12909 inhibited amphetamine-induced DA release by 74%. These experiments suggest that GBR12909 is an important prototypical medication to test the hypothesis that stimulant-induced euphoria is mediated by DA and, if the DA hypothesis is correct, a potential treatment agent for cocaine and methamphetamine abuse. Furthermore, this quantitative approach demonstrates a way of testing various treatment medications, including other forms of GBR12909 such as a decanoate derivative. Synapse 33:268–273, 1999. © 1999 Wiley-Liss, Inc.

GBR12909 (GBR) is a high-affinity, selective, and long-acting inhibitor of dopamine (DA) uptake that produces a persistent and noncompetitive blockade of DA transporters and substantially reduces cocaine-induced increases in extracellular DA in the nucleus accumbens of rats. Prior studies showed that intravenous infusion of GBR to Rhesus monkeys selectively reduced (1 mg/kg) and eliminated (3 mg/kg) cocaine self-administration. This study tested the hypothesis that doses of GBR that reduce cocaine self-administration in nonhuman primates produce significant occupation of DA transporters. DA transporters were quantitated in two baboons using [¹¹C]WIN35,428 and positron emission tomography (PET). Each baboon underwent paired control/blocked PET scans (performed on three separate study days, 3–4 weeks apart). On the first scan the baboon received saline (3 ml/kg) 90 minutes before the injection of the radiotracer. GBR (1 mg/kg i.v.) was infused 90 minutes before the second [¹¹C]WIN 35,428 study. The same experimental design was repeated with GBR doses of 3 and 10 mg/kg, respectively. Doses of 1 (n = 2), 3 mg/kg (n = 2), and 10 mg/kg (n = 2) reduced binding potential by 26, 53, and 72%, respectively. GBR was well tolerated in all baboons. These results demonstrate that doses of GBR that suppress cocaine self-administration in nonhuman primates also produce high occupancy of the DA transporter. These data strongly suggest that occupancy for the DA transporter by GBR explains its ability to attenuate cocaine-induced increases in extracellular DA and to suppress cocaine self-administration. Moreover, these data suggest that experimental human studies of orally administered GBR to test the DA hypothesis of cocaine addiction should use doses that produce at least 70% occupancy of the DA transporter. Synapse 32:44–50, 1999. © 1999 Wiley-Liss, Inc.

Positron emission tomography (PET) using 11C-inulin was demonstrated to be applicable to the clinical measurement of blood brain barrier permeability and cerebral interstitial fluid volume. Kinetic data were analyzed by application of a two compartment model, in which blood plasma and interstitial fluid spaces constitute the compartments. The blood activity contribution was subtracted from the PET count with the aid of the 11CO inhalation technique. The values we estimated in a human brain were in agreement with the reported values obtained for animal brains by the use of 14C-inulin.

We describe positron-emission tomography (PET) scintigraphic findings obtained using pyruvate-1-11C in eight patients with cerebral ischemic hypoxia or infarction. The extraction of11C by brain tissue from blood after an i.v. injection of11C-pyruvate was very rapid, being almost complete after a single circulatory passage. Most ischemic lesions were found to be more or less deficient with regard to11C-extraction capacity. With time, however, the ratio of11C in ischemic tissue to that in normal tissue was inverted, and the ischemic lesion appeared as a ‘hot’ area in the scintigram. Very old infarcts did not exhibit this phenomenon. These observations indicate the usefulness of an11C-pyruvate PET scan for the diagnosis of therapeutically restorable brain damage.

MDL 100,907 is a potent and selective antagonist of 5-HT2Aserotonin receptors. Animal studies suggest that MDL 100,907 may behave as an atypical antipsychotic drug. Positron emission tomograph (PET) using [11C]NMSP as the radiotracer was used to define the time course of 5-HT2receptor occupancy in the human frontal cerebral cortex after a single oral dose of MDL 100,907 (10 or 20 mg) in nine healthy subjects. After the baseline scan each subject was studied three times post dosing at various time points. 5-HT2occupancies were in the range of 70 and 90% after each dose. While the occupancy remains in this range over 24 hours after 20 mg MDL 100,907, it decreases by about 20% at 24 hours compared to the timepoint at 8 hours, when only 10 mg are administered (p< 0.05). Our results should allow determination of the appropriate dosing regimen for future trials in schizophrenic patients. [

Pyruvate-1-11C was prepared enzymatically by the exchange reaction of 11CO2 with the carboxyl group of pyruvic acid using pyruvate-ferredoxin oxidoreductase from Clostridium butyricum. 11C-Labeled pyruvate was purified by sublimation in specially made glassware. The radiochemical yield of pure pyruvate-1-11C was 80% 35 min after the end of bombardment. The distribution of 11C in tumor-bearing rabbits after an i.v. injection of pyruvate-1-11C was observed using a gamma camera. In contrast to normal organs, the tumor was positively visualized. We also conducted a number of successful clinical studies. A case of brain tumor which exhibited a positive image on positron-emission tomography (PET) using pyruvate-1-11C is presented.

Measurement of myocardial blood flow with13N-ammonia, a technique previously employed sucessfully in animal experiments, was introduced into clinical use to study patients with coronary artery disease. This advance has become possible by the development of a high resultion gated scan positron emission tomographic (PET) scanner equipped with a real time decay correction mechanism, HEADTOME-IV. The information obtainable includes myocardial size and wall motion as well as the absolute quantity of blood flow in various myocardial regions. The technique is simple but requires continuous arterial blood withdrawal for calculation of the arterial input function time integral. The alternative to this technique, i.e. the computation of intra left ventricular blood pool activity by PET is also discussed.

Carbon 14 from 14C-1-pyruvate injected intravenously into glioma-transplanted rats was incorporated into various compounds in the brain and in the tumor. In the brain the majority of activity was found in CO2 (60%), and minor activities were found in alanine, lactate (15%), glutamate, and aspartate, with decreasing order, 5 min after injection. In the tumor, at 5 min, the largest activity was in lactate (56%), and lower activities were found in CO2 (24%), alanine, glutamate, and aspartate. The total 14C concentration in the tumor was twice that in the brain at 5 min and 15 min. The result was in accordance with the prediction that in brain, where the mitochondrial function is active, 14C-1-pyruvate will be oxidized completely into 14CO2, and that in tumor, where the mitochondrial function is insufficient, 14C-1-pyruvate will be converted only into 14C-lactate and prevent further degradation. It may be assumed that this difference in the turnover of 14C of 14C-1-pyruvate between brain and tumor could constitute a basis for the ‘hot’ visualization of human brain tumor using cyclotron-produced 11C-1-pyruvate and positronemission tomography.