Quantitative analysis for estimating binding potential of the brain serotonin transporter with [11 C]McN5652.

SUMMARY: [11C](+)McN5652 is a selective serotonin reuptake inhibitor with subnanomolar potency for the serotonin transporter, and is currently being used for positron emission tomography studies. However, quantification of the regional [11C](+)McN5652 binding potential in vivo is a controversial issue because of its complex characteristics. The authors examined the regional differences in nonspecific binding and proposed simple methods for estimating the binding potential of [11C](+)McN5652. The regional difference in nonspecific binding was evaluated by the activity ratio of the thalamus compared with the cerebellum for inactive-isomer [11C](-)McN5652 and [11C](+)McN5652 saturation studies. The distribution volume of the thalamus was approximately 1.16 times larger than that of the cerebellum. The thalamus-to-cerebellum distribution volume ratio was estimated by nonlinear least square and graphical methods, with and without arterial input function. The graphical method with k2; without blood sampling was practical and most applicable for estimation of the distribution volume ratio because this method is more stable than the nonlinear least square method in the simulation study. Binding potential estimated with the distribution volume ratio of [11C](+)McN5652 and the correction with distribution volume ratio of [11C](-)McN5652 represent the most reliable parameters for the assessment of serotonin transporter binding.     

In vivo imaging of baboon and human dopamine transporters by positron emission tomography using [11C]WIN 35,428

[¹¹C]WIN 35,428 was evaluated as a specific in vivo radioligand for the dopamine transporter site by PET scanning in nonhuman primates and humans. In studies with a baboon (Papio anubis), [¹¹C]WIN 35,428 accumulated in brain regions containing dopamine transporters, i.e., the striata. This accumulation was Partially blocked by prior administration of (?)cocaine (4 mg/kg, i.v. ). Placement of a unilateral lesion of dopamine-containing nerve terminals with MPTP resulted in a unilateral reduction in [¹¹C]WIN 35,428 accumulation in the striatum on the side of the lesion. Imaging of D₂ dopamine receptors with [¹¹C]NMSP in the same MPTP-treated animals showed much less reduction in the postsynaptic D₂ dopamine receptors as compared to the much larger reduction in the dopamine transporters labeled with [¹¹C]WIN 35,428. A total of ten normal human volunteers (five males and five females) with ages ranging from 19 to 81 years were studied. The caudate/cerebellar and putamen/cerebellar ratios ranged from 4.4 to 5.7 90 min after injection of the tracer. Preliminary kinetic modeling with arterial plasma sampling resulted in an average binding potential (K₃/K₄) of 4.98 in the caudate nucleus and 5.13 in putamen. To demonstrate in vivo blockade with dopamine reuptake inhibitors, two subjects received prior oral doses of 6 mg mazindol. Subject 5 had significant reductions of 29% in the caudate/cerebellar ratio at 90 min, 35% in the putamen/cerebellar ratio at 90 min, 45% in the caudate k³/k⁴ ratio from 6.7 to 3.7, and 46% in the putamen k³/k⁴ from 4.7 to 2.5. Subject 8 had significant reductions of 20% in both the caudate/cerebellar ratio and the putamen/cerebellar ratio at 90 min. During the human PET studies, a number of neuropsychological tests and physiological measurements were performed. No significant changes were found after administration of the [¹¹C]WIN 35,428 alone. Taken together, these data indicate that [¹¹C]WIN 35,428 is a promising radioligand for future studies of neuropsychiatric disorders that involve the dopamine transporter site. © 1993 Wiley-Liss, Inc.

1 This article is a US government work and as such, is in the public domain in the United States of America.

     

Positron emission tomography imaging of the serotonin transporter in the pig brain using [11C](+)-McN5652 and S-([18F]fluoromethyl)-(+)-McN5652

S-([(18)F]fluoromethyl)-(+)-McN5652 ([(18)F](+)-FMe-McN5652) has recently been synthesized as a new potential radiotracer for positron emission tomography (PET) imaging of the 5-HT transporter. It is an analog of [(11)C](+)McN5652, which has been used in clinical PET studies for 5-HT transporter imaging. This article describes the comparison of these two radiotracers in pigs with respect to their in vivo binding characteristics. PET images revealed that the highest accumulation of both radiotracers was found in the ventral midbrain, thalamus, olfactory lobe, and pons which is consistent with the known density of 5-HT transporters. The specific binding was determined by subtracting the values of the inactive (-) enantiomers or of the occipital cortex from those obtained with [(11)C](+)McN5652 or [(18)F](+)-FMe-McN5652 in the time period between 75 and 115 min after radiotracer injection. The specific binding of the (18)F-labeled derivative was about 40% higher than that of the (11)C-labeled derivative. A strong inhibition of the specific binding was observed for both radiotracers after pretreatment with the selective 5-HT uptake inhibitor citalopram. [(18)F](+)-FMe-McN5652 showed faster kinetics than [(11)C](+)McN5652. It reached the binding equilibrium during a study length of 120 min, which was not the case for [(11)C](+)McN5652. It is concluded that [(18)F](+)-FMe-McN5652 is suitable for 5-HT transporter imaging with PET.     

Interaction between serotonin transporter and dopamine D2/D3 receptor radioligand measures is associated with harm avoidant symptoms in anorexia and bulimia nervosa

Individuals with anorexia nervosa (AN) and bulimia nervosa (BN) have alterations of measures of serotonin (5-HT) and dopamine (DA) function, which persist after long-term recovery and are associated with elevated harm avoidance (HA), a measure of anxiety and behavioral inhibition. Based on theories that 5-HT is an aversive motivational system that may oppose a DA-related appetitive system, we explored interactions of positron emission tomography (PET) radioligand measures that reflect portions of these systems. Twenty-seven individuals recovered (REC) from eating disorders (EDs) (7 AN–BN, 11 AN, 9 BN) and nine control women (CW) were analyzed for correlations between [¹¹C]McN5652 and [¹¹C]raclopride binding. There was a significant positive correlation between [¹¹C]McN5652 binding potential (BP_{non displaceable(ND)}) and [¹¹C]Raclopride BP_ND for the dorsal caudate, antero-ventral striatum (AVS), middle caudate, and ventral and dorsal putamen. No significant correlations were found in CW. [¹¹C]Raclopride BP_ND, but not [¹¹C]McN5652 BP_ND, was significantly related to HA in REC EDs. A linear regression analysis showed that the interaction between [¹¹C]McN5652 BP_ND and [¹¹C]raclopride BP_ND in the dorsal putamen significantly predicted HA. This is the first study using PET and the radioligands [¹¹C]McN5652 and [¹¹C]raclopride to show a direct relationship between 5-HT transporter and striatal DA D2/D3 receptor binding in humans, supporting the possibility that 5-HT and DA interactions contribute to HA behaviors in EDs.     

Effects of aging on serotonin transporter availability and its response to fluvoxamine in the living brain: PET study with [(11)C](+)McN5652 and [(11)C](-)McN5652 in conscious monkeys

Age-related changes in the serotonin transporter (SERT) in the living brains of conscious young (5.9 +/- 1.8 years old) and aged (19.0 +/- 3.3 years old) monkeys (Macaca mulatta) were evaluated in combination with [(11)C](+)McN5652 and its inactive enantiomer [(11)C](-)McN5652 by high-resolution positron emission tomography (PET). For the quantitative analysis of SERT binding in vivo, two serial PET scans with [(11)C](+)McN5652 and [(11)C](-)McN5652 were performed in the same animals in a day and the differences in radioactivities of [(11)C](+)McN5652 vs. [(11)C](-)McN5652 measured from 41-91 min postinjection were calculated as an estimate of specific ligand binding. Higher specific binding of SERT was observed in the thalamus and striatum, regions known to contain high densities of SERT by in vitro assay, with intermediate levels in the pons, hippocampus, cingulate gyrus, and cortical regions and lower levels in the cerebellum in both young and aged monkeys. Almost all regions assayed except the cerebellum showed significant age-related decreases in the specific binding of SERT, which showed reverse correlation with cortisol level in plasma. When the SERT blocker fluvoxamine (1 mg/kg) was administered intravenously 30 min after tracer injection, specific binding of SERT was displaced in both age groups. However, the degree of displacement was more marked in young than in aged monkeys. Cortisol level in plasma was significantly higher in aged than in young animals. These observations demonstrate the usefulness of the combined use of [(11)C](+)McN5652 and [(11)C](-)McN5652 as an indicator for the age-related changes in cortical SERT measured noninvasively by PET. In addition, these observations suggest that the age-related impairment of SERT sensitivity for fluvoxamine might be related to the reduced efficacy of antidepressant therapy in elderly patients with depression.     

Serotonin transporters in obsessive-compulsive disorder: a positron emission tomography study with [(11)C]McN 5652.

BACKGROUND: Serotonergic abnormalities have been hypothesized to contribute to obsessive-compulsive disorder (OCD). This study examined whether brain serotonin transporter (SERT) availability is altered in OCD using positron emission tomography (PET) and the SERT PET radiotracer [(11)C]McN 5652. METHODS: Eleven OCD subjects, free of psychiatric medications and comorbid depression, and 11 matched healthy control subjects underwent PET scans following injection of [(11)C]McN 5652 and magnetic resonance imaging (MRI) scans. Total distribution volumes (V(T)) were derived by kinetic analysis (one tissue compartment model) using the arterial input function. Two measures of SERT availability were computed: binding potential (BP) and specific to nonspecific partition coefficient (V(3)"). Groups were compared using region of interest (ROI) analysis and voxelwise analysis of spatially normalized parametric maps; ROIs were selected based on their relatively high SERT density and included subcortical (dorsal caudate, dorsal putamen, ventral striatum, midbrain, thalamus) and limbic (hippocampus, amygdala, anterior cingulate cortex) regions. RESULTS: No significant group differences were observed in [(11)C]McN 5652 BP or V(3)" in the ROIs. No significant group differences were detected in the voxelwise analysis of BP or V(3)" maps. CONCLUSIONS: OCD without comorbid depression, may not be associated with major changes in SERT availability in subcortical and limbic regions.     

PET imaging of the dopamine transporter in progressive supranuclear palsy and Parkinson's disease

OBJECTIVE: To differentiate the patterns of dopamine transporter loss between idiopathic PD and progressive supranuclear palsy (PSP). METHODS: We used the radiotracer [11C]-WIN 35,428 and PET. Regional striatal dopamine transporter binding was measured in the caudate, anterior putamen, and posterior putamen of six patients with L-dopa-responsive stage 2 PD, six patients with PSP, and six age-comparable healthy controls. RESULTS: In patients with idiopathic PD, the most marked abnormality was observed in the posterior putamen (77% reduction), whereas transporter density in the anterior putamen (60% reduction) and the caudate (44% reduction) was less affected. Unlike the patients with PD, the PSP group showed a relatively uniform degree of involvement in the caudate (40% reduction), anterior putamen (47% reduction), and posterior putamen (51% reduction). When posterior putamen/caudate ratios were calculated, these values were significantly lower in patients with PD than they were in patients with PSP (p = 0.0008) and the control group (p < 0.0001). CONCLUSIONS: Patients with PD have a more pronounced loss of dopamine transporters in the posterior putamen due to a subdivisional involvement of nigrostriatal dopaminergic projections in idiopathic PD. This technique is useful in the determination of neurochemical changes underlying PD and PSP, thus differentiating between them.     

Brain serotonin transporter density and aggression in abstinent methamphetamine abusers

CONTEXT: In animals, methamphetamine is known to have a neurotoxic effect on serotonin neurons, which have been implicated in the regulation of mood, anxiety, and aggression. It remains unknown whether methamphetamine damages serotonin neurons in humans. OBJECTIVE: To investigate the status of brain serotonin neurons and their possible relationship with clinical characteristics in currently abstinent methamphetamine abusers. DESIGN: Case-control analysis. SETTING: A hospital research center. PARTICIPANTS: Twelve currently abstinent former methamphetamine abusers (5 women and 7 men) and 12 age-, sex-, and education-matched control subjects recruited from the community. INTERVENTIONS: The brain regional density of the serotonin transporter, a structural component of serotonin neurons, was estimated using positron emission tomography and trans-1,2,3,5,6,10-beta-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]isoquinoline ([(11)C](+)McN-5652). Estimates were derived from region-of-interest and statistical parametric mapping methods, followed by within-case analysis using the measures of clinical variables. MAIN OUTCOME MEASURES: The duration of methamphetamine use, the magnitude of aggression and depressive symptoms, and changes in serotonin transporter density represented by the [(11)C](+)McN-5652 distribution volume. RESULTS: Methamphetamine abusers showed increased levels of aggression compared with controls. Region-of-interest and statistical parametric mapping analyses revealed that the serotonin transporter density in global brain regions (eg, the midbrain, thalamus, caudate, putamen, cerebral cortex, and cerebellum) was significantly lower in methamphetamine abusers than in control subjects, and this reduction was significantly inversely correlated with the duration of methamphetamine use. Furthermore, statistical parametric mapping analyses indicated that the density in the orbitofrontal, temporal, and anterior cingulate areas was closely associated with the magnitude of aggression in methamphetamine abusers. CONCLUSIONS: Protracted abuse of methamphetamine may reduce the density of the serotonin transporter in the brain, leading to elevated aggression, even in currently abstinent abusers.     

Kinetic analysis of [11C]McN5652: a serotonin transporter radioligand.

The impulse response function of a radioligand is the most fundamental way to describe its pharmacokinetics and to assess its tissue uptake and retention pattern. This study investigates the impulse response function of [11C](+)McN5652, a radioligand used for positron emission tomography (PET) imaging of the serotonin transporter (SERT) in the brain. Dynamic PET studies were performed in eight healthy volunteers injected with [11C](+)McN5652 and subsequently with its pharmacologically inactive enantiomer [11C](-)McN5652. The impulse response function was calculated by deconvolution analysis of regional time-activity curves, and its peak value (f(max)), its retention value at 75 minutes (fT), and its normalized retention (f(rel) = fT/f(max)) were obtained. Alternatively, compartmental models were applied to calculate the apparent total distribution volume (DV(T)) and its specific binding component (DV(S)). Both the noncompartmental (fT,f(rel)) and the compartmental parameters (DV) were investigated with and without correction for nonspecific binding by simple subtraction of the corresponding value obtained with [11C](-)McN5652. The impulse response function obtained by deconvolution analysis demonstrated high tracer extraction followed by a slow decline in the form of a monoexponential function. Statistical analysis revealed that the best compartmental model in terms of analysis of variance F and condition number of the parameter variance-covariance matrix was the one that was based on a single tissue compartment with parameters k1 and k2 and that also included the parameter of regional cerebral blood volume (BV). The parameter f(rel) demonstrated low between-subject variance (coefficient of variation [CV] = 19%), a midbrain to cerebellum ratio of 1.85, and high correlation with the known density of SERT (r = 0.787 where r is the coefficient of linear correlation between the parameter and the known density of SERT). After correction for nonspecific binding, f(rel) demonstrated further improvement in correlation (r = 0.814) and midbrain to cerebellum ratio (3.09). The variance of the distribution volumes was acceptable when the logarithmic transform lnDV was used instead of DV (17% for the three-parameter model), but correlation of this compartmental parameter was slightly less (r = 0.652 for the three-parameter model) than the correlation of the noncompartmental f(rel) with the known density of SERT, and the midbrain to cerebellum ratio was only 1.5 (uncorrected) and 1.8 (corrected). At the expense of increasing variance, the correlation was increased after correction for nonspecific binding using the inactive enantiomer (r = 0.694; CV = 22%). These results indicate that the kinetics of [11C](+)McN5652 can best be described by a one-tissue compartment model with three parameters (k1, k2, and BV), and that both the noncompartmental parameter f(rel) and the compartmental distribution volumes have the potential for quantitative estimation of the density of SERT. Further validation of the radioligand in experimental and clinical situations is warranted.     

Brain serotonin transporter distribution in subjects with impulsive aggressivity: a positron emission study with [11C]McN 5652

OBJECTIVE: The serotonin system is believed to play a role in modulating impulsivity and violence. Previous imaging studies have implicated the anterior cingulate and orbitofrontal cortex in impulsive aggression. This study evaluated regional serotonin transporter distribution in the brain of individuals with impulsive aggression by using positron emission tomography (PET) with the serotonin transporter PET radiotracer [(11)C]McN 5652. METHOD: Ten individuals with impulsive aggression and 10 age- and sex-matched healthy comparison subjects underwent [(11)C]McN 5652 PET. All individuals were medication free at the time of scanning. Regional total distribution volumes were derived by using a one-tissue compartment kinetic model with arterial input function. Outcome measures of serotonin transporter availability included the binding potential and the specific-to-nonspecific partition coefficient (V(3)'). RESULTS: Serotonin transporter availability was significantly reduced in the anterior cingulate cortex of individuals with impulsive aggression compared with healthy subjects, as noted by differences in both binding potential (mean=3.1 ml/g [SD=1.9] versus 5.0 ml/g [SD=2.0], respectively) and V(3)' (mean=0.15 [SD=0.09] versus 0.26 [SD=0.09]). In other regions examined, serotonin transporter density was nonsignificantly lower in individuals with impulsive aggression compared with healthy subjects. CONCLUSIONS: Pathological impulsive aggressivity might be associated with lower serotonergic innervation in the anterior cingulate cortex, a region that plays an important role in affective regulation.