Acute occupancy of brain serotonin transporter by sertraline as measured by [11C]DASB and positron emission tomography.

BACKGROUND: In vivo determination of serotonin transporter (5-HTT) occupancy by selective serotonin reuptake inhibitors (SSRI) using positron emission tomography (PET) can aid in determination of dosing. Previous studies used chronic SSRI administration that may down-regulate 5-HTT and used the cerebellum as reference region despite measurable 5-HTT. We examine the reference region and occupancy after acute sertraline dosing. METHODS: We conducted autoradiography of human postmortem cerebellum to determine an optimal reference region. We quantified 5-HTT binding using [(11)C]DASB and arterial input functions in 17 healthy volunteers. Baseline PET scans were followed by a scan 4-6 days after 25 mg to 100mg of daily sertraline. Several modeling methods and outcome measures were assessed. RESULTS: Cerebellar gray matter is the optimal reference region. Occupation of 5-HTT sites saturates at low plasma sertraline levels (K(D) = 1.9 ng/ml) with maximal occupancies of 106.8 +/- 8.3% across all brain regions. There is a weak correlation between oral sertraline and plasma sertraline. Occupancy measures vary based on the reference region and outcome measure used. CONCLUSIONS: Occupancy studies and postmortem autoradiography can help define the optimal reference region. Reference tissue modeling using the optimal reference region returns the same occupancy measures as those determined using an arterial input function.     

Serotonin transporter binding in bipolar disorder assessed using [11C]DASB and positron emission tomography.

BACKGROUND: Evidence from neuroimaging post-mortem, and genetic studies suggests that bipolar disorder (BD) is associated with abnormalities of the serotonin-transporter (5-HTT) system. Because of various limitations of these studies, however, it has remained unclear whether 5-HTT binding is abnormal in unmedicated BD-subjects. This study used PET and [(11)C]DASB, a radioligand that afforded higher sensitivity and specificity for the 5-HTT than previously available radioligands, to compare 5-HTT binding between BD and control subjects. METHODS: The 5-HTT binding-potential (BP) was assessed in 18 currently-depressed, unmedicated BD-subjects and 37 healthy controls using PET and [(11)C]DASB. RESULTS: In BD, the mean 5-HTT BP was increased in thalamus, dorsal cingulate cortex (DCC), medial prefrontal cortex and insula and decreased in the brainstem at the level of the pontine raphe-nuclei. Anxiety ratings correlated positively with 5-HTT BP in insula and DCC, and BP in these regions was higher in subjects manifesting pathological obsessions and compulsions relative to BD-subjects lacking such symptoms. Subjects with a history of suicide attempts showed reduced 5-HTT binding in the midbrain and increased binding in anterior cingulate cortex versus controls and to BD-subjects without attempts. CONCLUSIONS: This is the first study to report abnormalities in 5-HTT binding in unmedicated BD-subjects. The direction of abnormality in the brainstem was opposite to that found in the cortex, thalamus, and striatum. Elevated 5-HTT binding in the cortex may be related to anxiety symptoms and syndromes associated with BD.     

Serotonin transporter availability in patients with schizophrenia: a positron emission tomography imaging study with [11C]DASB.

BACKGROUND: Postmortem studies have reported several alterations in serotonin transporter (SERT) binding parameters in patients with schizophrenia. The aim of this study was to compare SERT availability in vivo in patients with schizophrenia and matched control subjects. METHODS: Ten medication-free patients with schizophrenia and 10 healthy subjects underwent positron emission tomography (PET) scans for 90 min after 11C-3-amino-4-(2-dimethylaminomethylphenylthio)benzonitrile ([11C]DASB) injection. Metabolite-corrected arterial input function was measured. Regional distribution volumes (mL/g) were derived with a two tissue compartment kinetic model. Outcome measures for SERT availability included binding potential (BP) and the specific-to-nonspecific equilibrium partition coefficient (V3'). Ten brain regions with high density of SERT and where SERT availability can be reliably quantified with [11C]DASB were included in the analysis. RESULTS: No significant differences were observed in regional BP or V3' between patients and control subjects. No significant relationships were observed between regional SERT availability and severity of positive, negative, and depressive symptoms. CONCLUSIONS: This study failed to detect alterations of SERT availability in patients with schizophrenia; however, this study does not rule out the possibility that schizophrenia might be associated with alterations of SERT density in the cortical regions, where the [11C]DASB-specific binding signal is too low for reliable quantification of SERT.     

Linearized reference tissue parametric imaging methods: application to [11C]DASB positron emission tomography studies of the serotonin transporter in human brain.

SUMMARY: The authors developed and applied two new linearized reference tissue models for parametric images of binding potential (BP) and relative delivery (R1) for [11C]DASB positron emission tomography imaging of serotonin transporters in human brain. The original multilinear reference tissue model (MRTM(O)) was modified (MRTM) and used to estimate a clearance rate (k'2) from the cerebellum (reference). Then, the number of parameters was reduced from three (MRTM) to two (MRTM2) by fixing k'2. The resulting BP and R1 estimates were compared with the corresponding nonlinear reference tissue models, SRTM and SRTM2, and one-tissue kinetic analysis (1TKA), for simulated and actual [11C]DASB data. MRTM gave k'2 estimates with little bias (<1%) and small variability (<6%). MRTM2 was effectively identical to SRTM2 and 1TKA, reducing BP bias markedly over MRTM(O) from 12-70% to 1-4% at the expense of somewhat increased variability. MRTM2 substantially reduced BP variability by a factor of two or three over MRTM or SRTM. MRTM2, SRTM2, and 1TKA had R1 bias <0.3% and variability at least a factor of two lower than MRTM or SRTM. MRTM2 allowed rapid generation of parametric images with the noise reductions consistent with the simulations. Rapid parametric imaging by MRTM2 should be a useful method for human [11C]DASB positron emission tomography studies.     

Novel 5-HTTLPR allele associates with higher serotonin transporter binding in putamen: a [(11)C] DASB positron emission tomography study.

BACKGROUND: The serotonin transporter (5-HTT)-linked polymorphic region (5-HTTLPR) has two frequent alleles, designated long (L), and short (S). The S allele is associated with lower levels of 5-HTT mRNA and lower 5-HTT expression in human cell lines. A functional single nucleotide variant was detected within L, designated L(A) and L(G). Only L(A) is associated with high levels of in vitro 5-HTT expression, whereas L(G) is low expressing and more similar to S. We examined the possible influence of the long (A/G) variant on 5-HTT density in the living human brain using 3-(11)C-amino-4-(2-dimethylaminomethylphenyl-sulfanyl) benzonitrile ([(11)C]DASB) positron emission tomography. METHODS: The 5-HTT binding potential (5-HTT BP), an index of 5-HTT density, was found in 43 healthy subjects genotyped for 5-HTTLPR long (A/G), and in an ethnically homogenous subsample of 30 Caucasian-Canadians. RESULTS: The L(A)/L(A) was associated with higher 5-HTT BP in putamen (p = .026, not corrected). This association became stronger in the Caucasian subsample (p = .004) and was significant even after correcting for multiple comparisons. CONCLUSIONS: The 5-HTTLPR long (A/G) polymorphism influences 5-HTT density leading to higher putamen 5-HTT BP in healthy L(A)/L(A) carriers of Caucasian ancestry. This finding extends the role of this polymorphism from in vitro reports of higher 5-HTT expression with the L(A)/L(A) genotype into in vivo brains of healthy human subjects.     

Elevated serotonin transporter binding in major depressive disorder assessed using positron emission tomography and [11C]DASB; comparison with bipolar disorder.

BACKGROUND: Altered serotonergic function is thought to play a role in the pathophysiology of major depressive episodes based upon evidence from neuroimaging, pharmacological, postmortem and genetic studies. It remains unclear, however, whether depressed samples that differ with respect to having shown a unipolar versus a bipolar illness course also would show distinct patterns of abnormalities within the serotonergic system. The current study compared serotonin transporter (5-HTT) binding between unipolar-depressives (MDD), bipolar-depressives (BD) and healthy-controls (HC) to assess whether the abnormalities in 5-HTT binding recently found in depressed subjects with BD extend to depressed subjects with MDD. METHODS: The 5-HTT binding-potential (BP) measured using positron emission tomography (PET) and [(11)C]DASB was compared between unmedicated, depressed subjects with MDD (n = 18) or BD (n = 18) and HC (n = 34). RESULTS: Relative to the healthy group both MDD and BD groups showed significantly increased 5-HTT BP in the thalamus (24%, 14%, respectively), insula (15%) and striatum (12%). The unipolar-depressives had elevated 5-HTT BP relative to both BD and HC groups in the vicinity of the periaqueductal gray (PAG, 20%, 22%, respectively). The bipolar-depressives had reduced 5-HTT BP relative to both HC and MDD groups in the vicinity of the pontine raphe nuclei. Depression-severity correlated negatively with 5-HTT BP in the thalamus in MDD-subjects. CONCLUSIONS: The depressed phases of MDD and BD both were associated with elevated 5-HTT binding in the insula, thalamus and striatum, but showed distinct abnormalities in the brainstem. The latter findings conceivably could underlie differences in the patterns of illness symptoms and pharmacological sensitivity observed between MDD and BD.     

Effect on [11C]DASB binding after tranylcypromine-induced increase in serotonin concentration: positron emission tomography studies in monkeys and rats

Several research groups have demonstrated that under specific conditions, in vivo neuroreceptor binding techniques can be used to measure acute changes in the concentrations of endogenous transmitters in the vicinity of neuroreceptors. The aim of this study was to investigate whether [(11)C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile ([(11)C]DASB) binding to the plasma membrane serotonin transporter (SERT) in the rhesus monkey and rat brain decreased after a pharmacologically-induced increase in the interstitial serotonin (5HT) concentration. Three rhesus monkeys were given repeated single boluses of [(11)C]DASB in sequential positron emission tomography (PET) experiments. Rats were given the tracer as a bolus dose plus a constant infusion. In vivo binding in both models was studied before and after presumably having increased interstitial 5HT concentrations using tranylcypromine (TCP), which inhibits the enzyme (monoamine oxidase, MAO), that degrades 5HT. The rat brain tissue was analyzed using high-performance liquid chromatography (HPLC) to determine the proportion of the PET signal comprising unchanged [(11)C]DASB. The binding of [(11)C]DASB in the thalamus decreased in both rhesus monkeys and rats after TCP administration. The possibility of using [(11)C]DASB as a tool for monitoring changes in endogenous serotonin concentrations merits further investigation.     

5-HTT binding in recovered depressed patients and healthy volunteers: a positron emission tomography study with [11C]DASB

OBJECTIVE: The serotonin transporter (5-HTT) is a key target for selective serotonin reuptake inhibitors and may be involved in the pathophysiology of major depression. It is now possible to image 5-HTT directly in the human brain, but results from studies of acutely depressed patients have been inconsistent. The purpose of this study was to determine whether abnormalities in 5-HTT might be present in recovered depressed patients. METHOD: The authors measured the binding potential of 5-HTT using [11C]DASB in conjunction with positron emission tomography (PET) in 24 medication-free, recovered depressed male patients and 20 healthy male comparison subjects. The regional estimates of binding potential were obtained using a metabolite-corrected plasma input function method followed by Logan analysis, with the cerebellum as a reference region. RESULTS: The authors found no significant difference in the binding potential of [11C]DASB between the recovered depressed patients and healthy comparison subjects in any of the brain regions (amygdala, anterior cingulate cortex, caudate nucleus, frontal cortex, hippocampus, insula, thalamus, and dorsal raphe) studied. CONCLUSIONS: Men who recover from depression have normal availability of 5-HTT in brain regions thought to be involved in the pathophysiology of depression. The findings therefore do not support the proposal that recurrent depression is associated with long-standing deficits in 5-HTT.     

Serotonin transporter availability in impulsive aggressive personality disordered patients: A PET study with [11C]DASB

Serotonin (5-HT) has consistently been implicated in the pathophysiology of impulsive aggression. In the current study, we tested the hypothesis that 5-HT transporter (5-HTT) binding is reduced in the anterior cingulate cortex (ACC) in impulsive aggressive patients. Additionally, we characterized pathological personality dimensions, with a specific focus on callousness (i.e. emotional indifference, a facet of psychopathy). Callousness is putatively positively correlated with presynaptic 5-HT, and thus could potentially confound the hypothesized negative relation between 5-HTT levels and trait aggression.We determined 5-HTT binding with positron emission tomography and [¹¹C]DASB in 29 patients with intermittent explosive disorder (IED-IR) and 30 controls. We assessed group differences in 5-HTT binding in the pregenual ACC, amygdala and subcortical regions and examined correlations between 5-HTT binding and clinical measures.There were no significant differences in 5-HTT binding between IED-IR patients and controls. Trait callousness exhibited a significant, positive correlation with ACC 5-HTT availability. Among IED-IR patients, a trend-level negative partial correlation was observed between trait aggression and ACC 5-HTT availability, while covarying for callousness and age. Exploratory analyses revealed a significant negative correlation between state aggression levels and 5-HTT availability in subcortical regions, namely striatum and thalamus.We did not confirm our hypothesis of lower ACC 5-HTT availability in impulsive aggressive patients, however, the positive correlation between callousness and ACC 5-HTT availability likely played a confounding role. Subtypes of aggression (e.g., reactive vs. proactive aggression), which are differentially associated with pathological personality dimensions such as callousness, may contribute to variability between 5-HT functioning and aggression.     

Selective serotonin reuptake inhibitor (SSRI) modulation of striatal dopamine measured with [11C]-raclopride and positron emission tomography

The effect of a pharmacologic increase in serotonin concentrations on striatal dopamine (D2) receptor availability has been measured in several studies using positron emission tomography (PET) and the radiotracer [11C]-raclopride as a method for the in vivo imaging of serotonin modulation of striatal dopamine in human subjects. These studies have shown that an acute increase in serotonin concentrations produced a decrease in striatal D2 receptor availability. The current study was undertaken to measure the effects of a more pharmacologically selective serotonergic agent compared to previous studies, the serotonin reuptake inhibitor, citalopram, on striatal D2 receptor availability. Twelve healthy control subjects underwent two PET scans performed on the same day following i.v. administration of saline (Scan 1) and citalopram (Scan 2, 40 mg, i.v.). The [11C]-raclopride data were analyzed with a graphical analysis method using the cerebellum as the input function. Plasma levels of citalopram, cortisol, and prolactin were measured. The citalopram concentrations peaked at the end of infusion (EOI) and remained relatively consistent from 30 min to 3 h postinfusion. An increase in cortisol and prolactin concentrations was observed from the EOI until 60 min after the EOI. A significant decrease in striatal D2 receptor availability was observed after citalopram infusion (-5%), presumably due to an increase in endogenous dopamine concentrations. In summary, i.v. administration of the selective serotonin reuptake inhibitor, citalopram, produced modest reductions in striatal D2 receptor availability, consistent with other human [11C]-raclopride studies using less pharmacologically selective serotonergic agents.     

Tryptophan depletion and serotonin loss in selective serotonin reuptake inhibitor-treated depression: an [(18)F] MPPF positron emission tomography study.

BACKGROUND: Recurrence of depressive symptoms after tryptophan depletion (TD) in selective serotonin reuptake inhibitor (SSRI)-treated depression is an important, unexplained phenomenon. With [(18)F] MPPF positron emission tomography (PET), serotonin (5-hydroxytryptamine, 5-HT) 1A receptor binding potential (5-HT(1A)BP) was measured after TD in various brain regions in citalopram-treated depression. This 5-HT(1A)BP measurement is sensitive to changes in extracellular 5-HT in animal models. METHODS: Eight remitted patients with major depressive disorder received [(18)F] MPPF PET scans twice: once after TD and once after sham depletion. Behavioral measures were evaluated with the Hamilton Depression Rating Scale and visual analog scales. RESULTS: No effect on regional 5-HT(1A)BP was observed after TD, despite an 86% decrease in total plasma tryptophan and transient depressive relapse in six of eight patients. CONCLUSIONS: Large-magnitude changes in extracellular 5-HT are not crucial for the mood effects observed in SSRI-treated subjects after TD. Therefore, greater consideration must be given to other mechanisms that involve vulnerability to small perturbations in extracellular 5-HT, such as impairment of signal transduction.     

Mapping of serotonin transporters by positron emission tomography with [11c]DASB in conscious common marmosets: Comparison with rhesus monkeys

The common marmoset (Callithrix jacchus) is unique among the primates in its small body size, reproductive efficacy, and characteristic social behavior, making it useful as an animal model in neuroscientific research. To assess the brain serotonergic systems, we investigated the binding of [¹¹C]‐3‐amino‐4‐(2‐dimetylaminomethyl‐phenylsulfanyl)‐benzonitrile ([¹¹C]DASB) to brain serotonin transporter (SERT) in conscious common marmosets using positron emission tomography (PET), and compared with findings for rhesus monkeys. Both species showed globally similar distribution patterns of [¹¹C]DASB uptake in the brain, with highest activity in the midline of the brain and lowest in the cerebellum, and higher activity in some subcortical regions than in surrounding cortex, while the common marmoset brain showed almost equal or rather higher binding potential (BP) values (BP_ND) in cortical regions and hippocampus, and lower BP_ND than the rhesus monkey brain in some subcortical regions. Test‐retest reproducibility of BP_ND at an interval of several months was high, indicating reliable and stable measurements of serotonin transporters in both species. These results suggest that SERT imaging by PET with [¹¹C]DASB under conscious state is valuable for investigating the physiological serotonergic functions in common marmosets (182). Synapse 2010. © 2010 Wiley‐Liss, Inc.     

青少年抑郁症5-羟色胺转运体基因多态性与疗效的相关研究

目的 在汉族抑郁症青少年中探索5-羟色胺转运体(5-HTT)基因多态与5-羟色胺再摄取抑制剂(SSRIs)疗效的关系.方法 研究对象为来自上海市精神卫生中心门诊及病房、符合美国精神障碍诊断与统计手册第四版(DSM-Ⅳ)抑郁症诊断标准、且接受SSRIs治疗的青少年抑郁症患者,平均年龄(15.9±1.7)岁,共有76例患者入组,脱落11例;于入组时和SSRIs治疗第2、4、6周末分别进行17项汉密尔顿抑郁量表(HAMD17)、汉密尔顿焦虑量表(HAMA)评定.应用PCR及PCR-RFLP技术对入组患者进行5-HTTLPR、5-HTT3'UTR多态基因分型.结果 SSRIs治疗有效组患者和无效组患者在5-HTTLPR多态及5-HTT3'UTR多态的基因型频率分布无明显差异(χ2=0.12,P=0.94;χ2=0.91,P=0.63)、等位基因频率分布也无明显差异(χ2=0.03,P=0.88;χ2=0.73,P=0.43).结论 在中国汉族青少年抑郁症患者群中5-HTTLPR、5-HTT3'UTR多态可能与SSRIs抗抑郁疗效之间无明显关联.     

High levels of serotonin transporter occupancy with low-dose clomipramine in comparative occupancy study with fluvoxamine using positron emission tomography

CONTEXT: Serotonin transporters (5-HTT) are regarded as one of the major therapeutic targets of antidepressants. However, there have only been a few studies about 5-HTT occupancy, and in particular, data concerning classical antidepressants are still limited. OBJECTIVE: To investigate the relationship between 5-HTT occupancy and a wide range of antidepressant dosing protocols.Design, Setting, and PARTICIPANTS: Antidepressant occupancies of 5-HTT were measured using positron emission tomography (PET) with [11C](+)McN5652. Twenty-seven healthy volunteers were measured with and without pretreatment with single low doses of antidepressants, and long-term doses were evaluated in 10 patients. Scan data were collected between December 12, 1995, and August 7, 2002, and data were analyzed during the 2001-2002 period at the National Institute of Radiological Sciences (Chiba, Japan).Intervention Four different doses of clomipramine hydrochloride (5-50 mg) and 3 different doses of fluvoxamine maleate (12.5-50 mg) were used for single administration. Long-term doses were 20 to 250 mg per day for clomipramine hydrochloride, and 25 to 200 mg per day for fluvoxamine maleate.Main Outcome Measure Occupancies in the thalamus were calculated using the individual baseline of [11C](+)McN5652 for single-dose studies and 2 long-term-dose studies, and the mean value of healthy volunteers as the baseline for 8 long-term-dose studies. The average data from inactive enantiomers [11C](-)McN5652 were used for the estimation of nonspecific binding. RESULTS: Occupancy of 5-HTT increased in a curvilinear manner. Even 10 mg of clomipramine hydrochloride showed approximately 80% occupancy, which was comparable with that of 50 mg of fluvoxamine maleate. Estimated median effective dose (ED50) of clomipramine hydrochloride was 2.67 mg for oral dose and 1.42 ng/mL for plasma concentration; those of fluvoxamine maleate were 18.6 mg and 4.19 ng/mL, respectively. CONCLUSIONS: Clinical doses of clomipramine and fluvoxamine occupied approximately 80% of 5-HTT, and dose escalation would have minimal effect on 5-HTT blockade. Ten milligrams of clomipramine hydrochloride was enough to occupy 80% of 5-HTT in vivo.     

In vivo quantification of serotonin transporters using [(11)C]DASB and positron emission tomography in humans: modeling considerations.

Positron emission tomography (PET) studies of the serotonin transporter (5-HTT) in the human brain are increasingly using the radioligand [(11)C]N, N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine. A variety of models have been applied to such data in several published articles; however to date, these models have not been validated with test-retest data. We recruited 11 healthy subjects and conducted two identical scans on each subject on the same day. We considered four different models (one- and two-tissue compartment kinetic models, likelihood estimation in graphical analysis (LEGA; a bias-free alternative to the graphical method), and basis pursuit) along with fast noniterative approximations to the kinetic models. We considered four different outcome measures (total volume of distribution (V(T)), binding potential with (BP) and without (BP(1)), free-fraction adjustment, and specific-to-nonspecific equilibrium partition coefficient (BP(2))). To assess the performance of each model, we compared results using six different metrics (percent difference (PD) and within-subject mean sum of squares for reproducibility, interclass coefficient for reliability, variance across subjects, identifiability based on bootstrap resampling of residuals for each method, and time stability analysis to determine minimal required scanning time). We considered analysis of both at the voxel level and at the region of interest (ROI) level and compared results from these two approaches to assess agreement. We determined that 100 mins of scanning time is adequate and that for ROI-level analysis, LEGA gives best results. Average PD is 5.51 for V(T), 20.7 for BP, 17.2 for BP(1), and 16.5 for BP(2) across all regions. For voxel-level analysis we determined that the one-tissue compartment noniterative model is best.     

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.     

Dual-[11C]tracer single-acquisition positron emission tomography studies.

The ability to study multiple physiologic processes of the brain simultaneously within the same subject would provide a new means to explore the interactions between neurotransmitter systems in vivo. Currently, examination of two distinct neuropharmacologic measures with positron emission tomography (PET) necessitates performing two separate scans spaced in time to allow for radionuclide decay. The authors present results from a dual-tracer PET study protocol using a single dynamic-scan acquisition where the injections of two tracers are offset by several minutes. Kinetic analysis is used to estimate neuropharmacologic parameters for both tracers simultaneously using a combined compartmental model configuration. This approach results in a large reduction in total study time of nearly 2 hours for carbon-11-labeled tracers. As multiple neuropharmacologic measures are obtained at nearly the same time, interventional protocols involving a pair of dual-tracer scans become feasible in a single PET session. Both computer simulations and actual human PET studies were performed using combinations of three different tracers: [11C]flumazenil, N-[11C]methylpiperidinyl propionate, and [ 11 C]dihydrotetrabenazine. Computer simulations of tracer-injection separations of 10 to 30 minutes showed the feasibility of the approach for separations down to 15 to 20 minutes or less. Dual-tracer PET studies were performed in 32 healthy volunteers using injection separations of 10, 15, or 20 minutes. Model parameter estimates for each tracer were similar to those obtained from previously performed single-injection studies. Voxel-by-voxel parametric images were of good quality for injections spaced by 20 minutes and were nearly as good for 15-minute separations, but were degraded noticeably for some model parameters when injections were spaced by only 10 minutes. The authors conclude that dual-tracer single-scan PET is feasible, yields accurate estimates of multiple neuropharmacologic measures, and can be implemented with a number of different radiotracer pairs.     

Elevated serotonin transporter binding in depressed patients with Parkinson's disease: A preliminary PET study with [11C]DASB

This study investigated whether abnormalities in serotonin transporter binding occur in Parkinson's disease (PD) patients with concurrent depression. We estimated serotonin transporter levels in seven clinically depressed early‐stage PD patients and in seven healthy matched‐control subjects during a single positron emission tomography (PET) scan with the serotonin transporter radioligand, [¹¹C]DASB. Depressed PD patients displayed a wide‐spread increase (8–68%) in [¹¹C]DASB specific binding outside of the striatum, which was significant in dorsolateral (37%) and prefrontal (68%) cortices. Elevated [¹¹C]DASB binding was positively correlated with depressive symptoms but not with disease severity or duration. Compatible with recent PET/[¹¹C]DASB findings in major depression, the present preliminary data suggest that increased [¹¹C]DASB binding, possibly reflecting greater serotonin transporter density (up‐regulation), might be a pathological feature of depression in Parkinson's disease—and possibly a characteristic of depressive illness in general. © 2008 Movement Disorder Society     

Binding characteristics of selective serotonin reuptake inhibitors with relation to emission tomography studies

When developing ligands for emission tomography studies, one of the major obstacles lies in the selection of ligand candidates. A previously unattended factor such as the influence of temperature on candidate ligand affinity is likely to play a role. By use of rat brain homogenates, the binding characteristics of [(3)H]-(S)-citalopram and [(3)H]-(+)-McN5652 and the receptor-ligand interaction at the serotonin transporter of 17 selective serotonin reuptake inhibitors were compared at 21 degrees C and 37 degrees C, respectively. Ligand logP values were also calculated. The ratios for K(i) at 37 degrees C vs. 21 degrees C varied between 0.2 and 2.2 for the selective serotonin reuptake inhibitors considered in this study, with most of the ligands displaying an inverse relationship between K(i) and temperature. Ten of the 17 selective serotonin reuptake inhibitors were found to have pK(i) values statistically significantly different at 21 degrees C compared to 37 degrees C (P < 0.05). The logP values ranged between 3.6 and 4.8, except for DASB, 5-iodo-6-nitroquipazine, and paroxetine where logP was 1.9, 2.2, and 5.0, respectively. K(d) was 0.71 nM at 37 degrees C and 0.31 nM at 21 degrees C for [(3)H]-(S)-citalopram. For [(3)H]-(+)-McN5652 K(d) was 0.11 nM at 37 degrees C and 0.08 nM at 21 degrees C. The association and dissociation was much faster for [(3)H]-(S)-citalopram as compared to [(3)H]-(+)-McN5652. It is concluded that temperature may affect K(d) differently and that in vitro dissociation may help to predict whether a given ligand may be useful in PET studies. LogP values do not per se predict the potential of a given ligand as an emission tomography tracer.