PET tracers and radiochemistry.

This paper provides a brief review of the radiochemistry of radiopharmaceuticals used in positron emission tomography (PET). It includes some history of PET, the basic formation of radionuclides in a cyclotron target, the processing of the precursor molecules into a useful PET radiotracer and the clinical significance and outlook for PET radiotracers. This review is based on a series of recent books and articles outlining the fundamental goals of PET and how radiochemistry plays a part in achieving these goals. It is also drawn from the literature that has been developed in PET over the last 30 years since PET became a research and valuable clinical tool. PET is a growing field and the clinical applications of the chemistry and technology have just begun to be explored. There is a great deal left to do in order to explore the full potential of PET in the clinic.

Non-MAO A binding of clorgyline in white matter in human brain.

Clorgyline is an irreversible inhibitor of monoamine oxidase (MAO A) which has been labeled with carbon-11 (C-11) and used to measure human brain MAO A with positron emission tomography (PET). In this study we compared [11C]clorgyline and deuterium-substituted [11C]clorgyline ([11C]clorgyline-D2) to better understand the molecular link between [11C]clorgyline binding and MAO A. In PET studies of five normal healthy volunteers scanned with [11C]clorgyline and [11C]clorgyline-D2 2 h apart, deuterium substitution generally produced the expected reductions in the brain uptake of [11C]clorgyline. However, the reduction was not uniform with the C-11 binding in white matter being significantly less sensitive to deuterium substitution than other brain regions. The percentages of the total binding attributable to MAO A is largest for the thalamus and smallest for the white matter and this is clearly seen in PET images with [11C]clorgyline-D2. Thus deuterium-substituted [11C]clorgyline selectively reduces the MAO A binding component of clorgyline in the human brain revealing non-MAO A binding which is most apparent in the white matter. The characterization of the non-MAO A binding component of this widely used MAO A inhibitor merits further investigation.

Species differences in [11C]clorgyline binding in brain.

[11C]Clorgyline selectively binds to MAO A in the human brain. This contrasts with a recent report that [11C]clorgyline (in contrast to other labeled MAO A inhibitors) is not retained in the rhesus monkey brain [4]. To explore this difference, we compared [11C]clorgyline in the baboon brain before and after clorgyline pretreatment and we also synthesized deuterium substituted [11C]clorgyline (and its nor-precursor) for comparison. [11C]Clorgyline was not retained in the baboon brain nor was it influenced by clorgyline pretreatment or by deuterium substitution, contrasting to results in humans. This suggests a species difference in the susceptibility of MAO A to inhibition by clorgyline and represents an unusual example of where the behavior of a radiotracer in the baboon brain does not predict its behavior in the human brain.

Prediction of cognitive decline in normal elderly subjects with 2-[(18)F]fluoro-2-deoxy-D-glucose/poitron-emission tomography (FDG/PET).

Neuropathology studies show that patients with mild cognitive impairment (MCI) and Alzheimer's disease typically have lesions of the entorhinal cortex (EC), hippocampus (Hip), and temporal neocortex. Related observations with in vivo imaging have enabled the prediction of dementia from MCI. Although individuals with normal cognition may have focal EC lesions, this anatomy has not been studied as a predictor of cognitive decline and brain change. The objective of this MRI-guided 2-[(18)F]fluoro-2-deoxy-d-glucose/positron-emission tomography (FDG/PET) study was to examine the hypothesis that among normal elderly subjects, EC METglu reductions predict decline and the involvement of the Hip and neocortex. In a 3-year longitudinal study of 48 healthy normal elderly, 12 individuals (mean age 72) demonstrated cognitive decline (11 to MCI and 1 to Alzheimer's disease). Nondeclining controls were matched on apolipoprotein E genotype, age, education, and gender. At baseline, metabolic reductions in the EC accurately predicted the conversion from normal to MCI. Among those who declined, the baseline EC predicted longitudinal memory and temporal neocortex metabolic reductions. At follow-up, those who declined showed memory impairment and hypometabolism in temporal lobe neocortex and Hip. Among those subjects who declined, apolipoprotein E E4 carriers showed marked longitudinal temporal neocortex reductions. In summary, these data suggest that an EC stage of brain involvement can be detected in normal elderly that predicts future cognitive and brain metabolism reductions. Progressive E4-related hypometabolism may underlie the known increased susceptibility for dementia. Further study is required to estimate individual risks and to determine the physiologic basis for METglu changes detected while cognition is normal.

Hippocampal formation glucose metabolism and volume losses in MCI and AD.

We used MRI volume sampling with coregistered and atrophy corrected FDG-PET scans to test three hypotheses: 1) hippocampal formation measures are superior to temporal neocortical measures in the discrimination of normal (NL) and mild cognitive impairment (MCI); 2) neocortical measures are most useful in the separation of Alzheimer disease (AD) from NL or MCI; 3) measures of PET glucose metabolism (MRglu) have greater diagnostic sensitivity than MRI volume. Three groups of age, education, and gender matched NL, MCI, and AD subjects were studied. The results supported the hypotheses: 1) entorhinal cortex MRglu and hippocampal volume were most accurate in classifying NL and MCI; 2) both imaging modalities identified the temporal neocortex as best separating MCI and AD, whereas widespread changes accurately classified NL and AD; 3) In most between group comparisons regional MRglu measures were diagnostically superior to volume measures. These cross-sectional data show that in MCI hippocampal formation changes exist without significant neocortical changes. Neocortical changes best characterize AD. In both MCI and AD, metabolism reductions exceed volume losses.

Resting brain metabolic activity in a 4 tesla magnetic field.

MRI is a major tool for mapping brain function; thus it is important to assess potential effects on brain neuronal activity attributable to the requisite static magnetic field. This study used positron emission tomography (PET) and (18)F-deoxyglucose ((18)FDG) to measure brain glucose metabolism (a measure of brain function) in 12 subjects while their heads were in a 4 T MRI field during the (18)FDG uptake period. The results were compared with those obtained when the subjects were in the earth's field (PET scanner), and when they were in a simulated MRI environment in the PET instrument that imitated the restricted visual field of the MRI experiment. Whole-brain metabolism, as well as metabolism in occipital cortex and posterior cingulate gyrus, was lower in the real (4 T) and simulated (0 T) MRI environments compared with the PET. This suggests that the metabolic differences are due mainly to the visual field differences characteristic of the MRI and PET instruments. We conclude that a static magnetic field of 4 T does not in itself affect this fairly sensitive measure of brain activity.

Cocaine abusers show a blunted response to alcohol intoxication in limbic brain regions.

UNLABELLED: Cocaine and alcohol are frequently used simultaneously and this combination is associated with enhanced toxicity. We recently showed that active cocaine abusers have a markedly enhanced sensitivity to benzodiazepines. Because both benzodiazepines and alcohol facilitate GABAergic neurotransmission we questioned whether cocaine abusers would also have an enhanced sensitivity to alcohol that could contribute to the toxicity. In this study we compared the effects of alcohol (0.75 g/kg) on regional brain glucose metabolism between cocaine abusers (n = 9) and controls (n = 10) using PET and FDG. Alcohol significantly decreased whole brain metabolism and this effect was greater in controls (26+/-6%) than in abusers (17+/-10%) even though they had equivalent levels of alcohol in plasma. Analysis of the regional measures showed that cocaine abusers had a blunted response to alcohol in limbic regions, cingulate gyrus, medial frontal and orbitofrontal cortices. CONCLUSIONS: The blunted response to alcohol in cocaine abusers contrasts with their enhanced sensitivity to benzodiazepines suggesting that targets other than GABA-benzodiazepine receptors are involved in the blunted sensitivity to alcohol and that the toxicity from combined cocaine-alcohol use is not due to an enhanced sensitivity to alcohol in cocaine abusers. The blunted response to alcohol in limbic regions and in cortical regions connected to limbic areas could result from a decreased sensitivity of reward circuits in cocaine abusers.

Mechanism of nitrogen-13-labeled ammonia formation in a cryogenic water target.

Methods for producing N-13 ammonia via the 16O(p,alpha)13N nuclear reaction utilizing a cryogenic target have been investigated. These targets included frozen carbon dioxide and pure frozen water. Results from these targets were compared with the more traditional liquid water target with and without additives. A very dramatic difference was found between the pure water target in the frozen state when compared with the liquid state. When frozen, more than 95% of the nitrogen-13 activity is in the chemical form of ammonia at all radiation doses. In contrast, the liquid water target yielded predominately nitrates and nitrites at high radiation doses. When frozen carbon dioxide was irradiated under these conditions, more than 95% of the nitrogen-13 activity was in the form of nitrate and nitrite. The nitrogen oxides remained on the surface of the target and could be easily removed from the surface with pure water. The wash solution was converted to [13N]ammonia using the DeVarda's alloy method for reduction. It was determined that levels of [13N]ammonia sufficient for diagnostic medical procedures could be produced directly using the frozen water targets or from frozen carbon dioxide with a wet chemical reduction. These results have significance particularly in the design of targetry for low-energy, high-beam current accelerators, because targets of this design can be used with either no vacuum isolation window or a very thin window. The substitution of carbon-13-enriched carbon dioxide for natural carbon dioxide gives access to the 13C(p,n)13N nuclear reaction, which allows protons energies as low as 6 MeV to be used to produce useable quantities of N-13 ammonia. The mechanism of these reactions has been explored to determine why there are such dramatic differences in the product distribution between the frozen state and the liquid or gaseous state.

Cryogenic target design considerations for the production of [18F]fluoride from enriched [18O]carbon dioxide.

Four cryogenic target designs are described for the production of fluorine-18 in the chemical form of fluoride using oxygen-18-enriched carbon dioxide gas utilizing the (18)O(p,n)18F nuclear reaction. The targets are conical in shape and made of copper or silver and the carbon dioxide is frozen into the cone at liquid nitrogen temperatures. Three of the targets (2 copper and 1 silver) have four cooling fins extending radially and are different lengths, and one target has only a single heat sink at the rear of the cone. The targets with four cooling fins could be run with 17.4 MeV protons incident on the target material at a beam current of 25 microA with no detectable volatilization of the target material, although yields did decrease slightly when compared with lower current runs. The target with the single cooling block showed volatilization at about 8 microA. The two copper targets of different lengths did not show a difference in the volatilization of the target material at the beam current limit of our cyclotron (25 microA). The shorter target did maintain production with a lower amount of gas frozen into the target, while the longer target maintained production at higher beam currents. Targets of this type are compatible with low energy, high current accelerators because very thin windows may be used.

Yield measurements for the 11B(p,n)11C and the 10B(d,n)11C nuclear reactions.

The yields from the 11B(p,n)11C nuclear reactions have been measured over the energy range of 0-28.6 MeV. The yields from the 10B(d,n)11C nuclear reactions have been measured over the energy range of 0-21.5 MeV. Cross-section values were derived from the yield data. The yield measurements were carried out on sealed samples of boron powder isotopically enriched to greater than 93%. The target holders were constructed of aluminum and each contained 50 mg of boron powder to achieve high energy resolution, but with sufficient material to ensure accurate cross-section measurements. 11C yields were determined by decay-curve analysis. Our data show that at energies below 5 MeV, the 11B(p,n)11C nuclear reaction can be expected to produce 250 mCi of 11C (based on a 30 min irradiation at a beam current of 100 microA).

Carbon-11 labelled ketamine-synthesis, distribution in mice and PET studies in baboons.

No-carrier-added (NCA)[11C](+/-)-ketamine (2a) and its enantiomers (+)-2b and (-)-2c were synthesized by methylation of the corresponding norketamine (1a-c) with [11C]H3I in an overall radiochemical yield of 20% (EOB) with specific activities of 0.35-0.45 Ci/mumol at EOB in a synthesis time of 40 min from EOB. Compound 2a was metabolized rapidly in mouse brain and labeled metabolites appeared in baboon plasma. PET studies of compounds 2a-c in a baboon showed that influx of compounds 2a-c into the brain was high for the first few min but radioactivity then declined rapidly. Although the retention of radioactivity in the baboon striatum was not significantly different for 2a-c 20 min post-injection, graphical analysis of time-activity data for each enantiomer and for the racemate in baboon striatum suggested that (+)-ketamine may interact with receptors slightly more effectively than its (-)-enantiomer or racemate. However, due to its rapid metabolism in the brain and a similar uptake in the striatum and cerebellum, [11C]ketamine may not be an ideal tracer for studying NMDA receptor with PET.

Brain monoamine oxidase A inhibition in cigarette smokers.

Several studies have documented a strong association between smoking and depression. Because cigarette smoke has been reported to inhibit monoamine oxidase (MAO) A in vitro and in animals and because MAO A inhibitors are effective antidepressants, we tested the hypothesis that MAO A would be reduced in the brain of cigarette smokers. We compared brain MAO A in 15 nonsmokers and 16 current smokers with [11C]clorgyline and positron emission tomography (PET). Four of the nonsmokers were also treated with the antidepressant MAO inhibitor drug, tranylcypromine (10 mg/day for 3 days) after the baseline PET scan and then rescanned to assess the sensitivity of [11C]clorgyline binding to MAO inhibition. MAO A levels were quantified by using the model term lambda k3 which is a function of brain MAO A concentration. Smokers had significantly lower brain MAO A than nonsmokers in all brain regions examined (average reduction, 28%). The mean lambda k3 values for the whole brain were 0.18 +/- 0.04 and 0.13 +/- 0.03 ccbrain (mlplasma)-1 min-1 for nonsmokers and smokers, respectively; P < 0.0003). Tranyl-cypromine treatment reduced lambda k3 by an average of 58% for the different brain regions. Our results show that tobacco smoke exposure is associated with a marked reduction in brain MAO A, and this reduction is about half of that produced by a brief treatment with tranylcypromine. This suggests that MAO A inhibition needs to be considered as a potential contributing variable in the high rate of smoking in depression and in the development of more effective strategies for smoking cessation.

Measuring age-related changes in dopamine D2 receptors with 11C-raclopride and 18F-N-methylspiroperidol.

This study investigates the rate of age-related dopamine D2 receptor loss as determined by positron emission tomography (PET) and 11C-raclopride and compares it with D2 loss previously estimated with 18F-N-methylspiroperidol (NMS). Dopamine D2 receptors were measured with 11C-raclopride in 24 healthy volunteers (24-73 years of age) using the ratio of the distribution volume in striatum to that in cerebellum (Bmax/Kd + 1). The results were compared with those obtained in 20 healthy male volunteers (20-49 years of age) in whom D2 receptors were measured with NMS using the ratio index (slope of the striatum-to-cerebellum ratio as a function of time). Findings of correlational analysis between age and dopamine D2 receptor availability were significant for both ligands. Estimates of dopamine D2 receptor loss per decade corresponded to 7.9% for the 11C-raclopride study and 7.8% for the NMS study. Both ligands documented significant age-related decreases in dopamine D2 receptors that occurred relatively early in life (40 years of age).

Opioid receptor imaging and displacement studies with [6-O-[11C] methyl]buprenorphine in baboon brain.

Buprenorphine (BPN) is a mixed opiate agonist-antagonist used as an analgesic and in the treatment of opiate addiction. We have used [6-O-[11C]methyl]buprenorphine ([11C]BPN) to measure the regional distribution in baboon brain, the test-retest stability of repeated studies in the same animal, the displacement of the labeled drug by naloxone in vivo, and the tissue distribution in mice. The regional distribution of radioactivity in baboon brain determined with PET was striatum > thalamus > cingulate gyrus > frontal cortex > parietal cortex > occipital cortex > cerebellum. This distribution corresponded to opiate receptor density and to previously published data (37). The tracer uptake in adult female baboons showed no significant variation in serial scans in the same baboon with no intervention in the same scanning session. HPLC analysis of baboon plasma showed the presence of labeled metabolites with 92% +/- 2.2% and 43% +/- 14.4% of the intact tracer remaining at 5 and 30 min, respectively. Naloxone, an opiate receptor antagonist, administered 30-40 min after tracer injection at a dose of 1.0 mg/kg i.v., reduced [11C]BPN binding in thalamus, striatum, cingulate gyrus, and frontal cortex to values 0.25 to 0.60 of that with no intervention. There were minimal (< 15%) effects on cerebellum. Naloxone treatment significantly reduced the slope of the Patlak plot in receptor-containing regions. These results demonstrate that [11C]BPN can be displaced by naloxone in vivo, and they affirm the feasibility of using this tracer and displacement methodology for short-term kinetics studies with PET. Mouse tissue distribution data were used to estimate the radiation dosimetry to humans. The critical organ was the small intestine, with a radiation dose estimate to humans of 117 nrad/mCi.

Inhibition of monoamine oxidase B in the brains of smokers.

The massive health problem associated with cigarette smoking is exacerbated by the addictive properties of tobacco smoke and the limited success of current approaches to cessation of smoking. Yet little is known about the neuropharmacological actions of cigarette smoke that contribute to smoking behaviour, or why smoking is so prevalent in psychiatric disorders and is associated with a decreased risk of Parkinson's disease. Here we report that brains of living smokers show a 40% decrease in the level of monoamine oxidase B (MAO B; EC 1.4.3.4) relative to non-smokers or former smokers. MAO B is involved in the breakdown of dopamine, a neurotransmitter implicated in reinforcing and motivating behaviours as well as movement. MAO B inhibition is therefore associated with enhanced activity of dopamine, as well as with decreased production of hydrogen peroxide, a source of reactive oxygen species. We propose that reduction of MAO B activity may synergize with nicotine to produce the diverse behavioural and epidemiological effects of smoking.

[18F]haloperidol binding in baboon brain in vivo.

The binding of [18F]haloperidol to dopamine D2 and to sigma recognition sites in baboon brain was examined using positron emission tomography (PET). Studies were performed at baseline and after treatment with either haloperidol (to evaluate saturability), (+)-butaclamol (which has specificity for dopamine D2 receptors) or (-)-butaclamol (which has specificity for sigma sites). Binding was widespread. Treatment with (-)-butaclamol had no effect, whereas (+)-butaclamol selectively reduced the uptake in striatum. Haloperidol increased the clearance rate from all brain regions. These results indicate that the binding profile of [18F]haloperidol does not permit the selective examination of either dopamine D2 or sigma sites using PET.

A new PET ligand for the dopamine transporter: studies in the human brain.

UNLABELLED: Carbon-11-d-threo-methylphenidate, the active enantiomer of methylphenidate (ritalin), has been shown to bind uniquely to the dopamine transporter in the baboon brain. This study characterizes its binding in the human brain and measures its test-retest reproducibility. METHODS: Studies were done in seven normal controls, each of whom was scanned with [11C]d-threomethylphenidate on two different occasions. Six subjects were scanned twice 3-5 wk apart without intervention to assess reproducibility. One subject was scanned sequentially before and after treatment with methylphenidate to assess binding saturability. Graphical analysis was used to obtain tissue distribution volumes (DV). The ratio of the DV in the basal ganglia (BG) to that in cerebellum (CB) (DVBG/DVCB), which corresponds to (Bmax/Kd) + 1 was used to estimate dopamine transporter availability. RESULTS: Highest tracer uptake occurred in the basal ganglia, where activity peaked 7-11 min postinjection. The half-clearance time for the tracer in brain regions other than the basal ganglia was 74 min. In the basal ganglia, only 10%-15% of the activity had cleared at 74 min. Time-activity curves for [11C]d-threo-methylphenidate in the basal ganglia and cerebellum were highly reproducible. The average percent change for the absolute value for DVBG/DVCB was 6.5% +/- 4% (range 0-12%). Methylphenidate pretreatment decreased basal ganglia uptake but not cortical or cerebellar binding and reduced DVBG/DVCB by 62% and Bmax/Kd by 91%. CONCLUSION: These studies demonstrate that [11C]d-threo-methylphenidate binding in the human brain is reversible, highly reproducible and saturable. Thus, it is an appropriate PET ligand to measure dopamine transporter availability.

Plasma input function determination for PET using a commercial laboratory robot.

A commercial laboratory robot system (Zymate PyTechnology II Laboratory Automation System) was interfaced to standard and custom laboratory equipment and programmed to perform rapid radiochemical assays necessary for plasma input function determination in quantitative PET studies in humans and baboons. A Zymark XP robot arm was used to carry out two assays: (1) the determination of total plasma radioactivity concentrations in a series of small-volume whole blood samples and (2) the determination of unchanged (parent) radiotracer in plasma using only solid phase extraction methods. Steady state robotic throughput for determination of total plasma radioactivity in whole blood samples (0.350 mL) is 14.3 samples/h, which includes automated centrifugation, pipetting, weighing and radioactivity counting. Robotic throughput for the assay of parent radiotracer in plasma is 4-6 samples/h depending on the radiotracer. Percents of total radioactivities present as parent radiotracers at 60 min, postinjection of 25 +/- 5.0 (N = 25), 26 +/- 6.8 (N = 68), 13 +/- 4.4 (N = 30), 32 +/- 7.2 (N = 18), 16 +/- 4.9 (N = 20), were obtained for carbon-11 labeled benztropine, raclopride, methylphenidate, SR 46349B (trans, 4-[(3Z)3-(2-dimethylamino-ethyl) oxyimino-3 (2-fluorophenyl)propen-1-yl]phenol), and cocaine respectively in baboon plasma and 84 +/- 6.4 (N = 9), 18 +/- 11 (N = 10), 74 +/- 5.7 (N = 118) and 16 +/- 3.7 (N = 18) for carbon-11 labeled benztropine, deprenyl, raclopride, and methylphenidate respectively in human plasma. The automated system has been used for more than 4 years for all plasma analyses for 7 different C-11 labeled compounds used routinely in our laboratory. The robotic radiotracer assay runs unattended and includes automated cleanup procedures that eliminates all human contact with plasma-contaminated containers.

Selective reduction of radiotracer trapping by deuterium substitution: comparison of carbon-11-L-deprenyl and carbon-11-deprenyl-D2 for MAO B mapping.

UNLABELLED: Recent human PET studies with the monoamine oxidase B (MAO B) tracer [11C]L-deprenyl show that the rapid rate of radiotracer trapping relative to transport reduces the sensitivity of the tracer in regions of high MAO B concentration. This study investigates the use of deuterium substituted L-deprenyl ([11C]L-deprenyl-D2) to reduce the rate of trapping in tissue and to improve sensitivity. METHODS: Five normal subjects (43-64 yr) were studied with [11C]L-deprenyl and [11C]L-deprenyl-D2 on the same day. Time-activity data from different brain regions and the arterial plasma were analyzed using a three-compartment model as well as graphical analysis for irreversible systems. RESULTS: For both tracers, maximum radioactivity accumulation occurred at about 5 min. For [11C]L-deprenyl, 11C concentration peaked at 5 min and remained constant throughout the study. With [11C]L-deprenyl-D2, peak 11C concentration also occurred at about 5 min but was followed by an initial washout. Carbon-11 concentration generally plateaued from 30 to 60 min. The plateau for [11C]L-deprenyl was higher than the plateau for [11C]L-deprenyl-D2. Data analysis by a three-compartment model and by graphical analysis showed that deuterium substitution: (a) does not affect plasma to tissue transport (K1); (b) reduces the rate of trapping of 11C in all brain regions; (c) facilitates the separation of model terms related to radiotracer delivery from radiotracer trapping in tissue; and (d) improves tracer sensitivity. CONCLUSION: This study demonstrates that deuterium substitution causes a significant reduction in the rate of trapping of labeled deprenyl, providing a direct link between radiotracer uptake and MAO B in the human brain and enhancing tracer sensitivity to changes in MAO B concentration.

Carbon-11-cocaine binding compared at subpharmacological and pharmacological doses: a PET study.

UNLABELLED: We have characterized cocaine binding in the brain to a high-affinity site on the dopamine transporter using PET and tracer doses of [11C]cocaine in the baboon in vivo. The binding pattern, however, of cocaine at tracer (subpharmacological) doses may differ from that observed when the drug is taken in behaviorally active doses particularly since in vitro studies have shown that cocaine also binds to low affinity binding sites. METHODS: PET was used to compare and characterize [11C]cocaine binding in the baboon brain at low subpharmacological (18 micrograms average dose) and at pharmacological (8000 micrograms) doses. Serial studies on the same day in the same baboon were used to assess the reproducibility of repeated measures and to assess the effects of drugs which inhibit the dopamine, norepinephrine and serotonin transporters. Time-activity curves from brain and the arterial plasma input function were used to calculate the steady-state distribution volume (DV). RESULTS: At subpharmacological doses, [11C]cocaine had a higher binding and slower clearance in striatum than in other brain regions. At pharmacological doses, [11C]cocaine had a more homogeneous distribution. Bmax/Kd for sub-pharmacological [11C]cocaine corresponded to 0.5-0.6 and for pharmacological [11C]cocaine it corresponded to 0.1-0.2. Two-point Scatchard analysis gave Bmax = 2300 pmole/g and Kd' = 3600 nM. Bmax/Kd for sub-pharmacological doses of [11C]cocaine was decreased by cocaine and drugs that inhibit the dopamine transporter, to 0.1-0.2, but not by drugs that inhibit the serotonin or the norepinephrine transporter. None of these drugs changed Bmax/Kd for a pharmacological dose of [11C]cocaine. CONCLUSION: At subpharmacological doses, [11C]cocaine binds predominantly to a high-affinity site on the dopamine transporter.