Mapping human brain fatty acid amide hydrolase activity with PET

Endocannabinoid tone has recently been implicated in a number of prevalent neuropsychiatric conditions. [¹¹C]CURB is the first available positron emission tomography (PET) radiotracer for imaging fatty acid amide hydrolase (FAAH), the enzyme which metabolizes the prominent endocannabinoid anandamide. Here, we sought to determine the most suitable kinetic modeling approach for quantifying [¹¹C]CURB that binds selectively to FAAH. Six healthy volunteers were scanned with arterial blood sampling for 90 minutes. Kinetic parameters were estimated regionally using a one-tissue compartment model (TCM), a 2-TCM with and without irreversible trapping, and an irreversible 3-TCM. The 2-TCM with irreversible trapping provided the best identifiability of PET outcome measures among the approaches studied (coefficient of variation (COV) of the net influx constant K_i and the composite parameter λk₃ (λ=K₁/k₂) <5%, and COV(k₃)<10%). Reducing scan time to 60 minutes did not compromise the identifiability of rate constants. Arterial spin labeling measures of regional cerebral blood flow were only slightly correlated with K_i, but not with k₃ or λk₃. Our data suggest that λk₃ is sensitive to changes in FAAH activity, therefore, optimal for PET quantification of FAAH activities with [¹¹C]CURB. Simulations showed that [¹¹C]CURB binding in healthy subjects is far from a flow-limited uptake.     

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.     

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.     

Imaging of dopamine D2/3 agonist binding in cocaine dependence: a [11C]NPA positron emission tomography study

Objective: Positron emission tomography (PET) studies performed with [¹¹C]raclopride have consistently reported lower binding to D_2/3 receptors and lower amphetamine‐induced dopamine (DA) release in cocaine abusers relative to healthy controls. A limitation of these studies that were performed with D_2/3 antagonist radiotracers such as [¹¹C]raclopride is the failure to provide information that is specific to D_2/3 receptors configured in a state of high affinity for the agonists (i.e., D_2/3 receptors coupled to G‐proteins, D_{2/3 HIGH}). As the endogenous agonist DA binds with preference to D_{2/3 HIGH} relative to D_{2/3 LOW} receptors (i.e., D_2/3 receptors uncoupled to G‐proteins) it is critical to understand the in vivo status of D_{2/3 HIGH} receptors in cocaine dependence. Thus, we measured the available fraction of D_{2/3 HIGH} receptors in 10 recently abstinent cocaine abusers (CD) and matched healthy controls (HC) with the D_2/3 antagonist and agonist PET radiotracers [¹¹C]raclopride and [¹¹C]NPA. Methods: [¹¹C]raclopride and [¹¹C]NPA binding potential (BP) (BP_ND) in the striatum were measured with kinetic analysis using the arterial input function. The available fraction of D_{2/3 HIGH} receptors, i.e., % R_HIGH available = D_{2/3 HIGH}/(D_{2/3 HIGH} + D_{2/3 LOW}) was then computed as the ratio of [¹¹C]NPA BP_ND/[¹¹C]raclopride BP_ND. Results: No differences in striatal [¹¹C]NPA BP_ND (HC = 1.00 ± 0.17; CD = 0.97 ± 0.17, P = 0.67) or available % R_HIGH (HC = 39% ± 5%; CD = 41% ± 5%, P = 0.50) was observed between cocaine abusers and matched controls. Conclusions: The results of this [¹¹C]NPA PET study do not support alterations in D_{2/3 HIGH} binding in the striatum in cocaine dependence. Synapse, 2011. © 2011 Wiley‐Liss, Inc.     

Kinetic modeling of the monoamine oxidase B radioligand [11C]SL25.1188 in human brain with high-resolution positron emission tomography

This article describes the kinetic modeling of [¹¹C]SL25.1188 ([(S)-5-methoxymethyl-3-[6-(4,4,4-trifluorobutoxy)-benzo[d]isoxazol-3-yl]-oxazolidin-2-[¹¹C]one]) binding to monoamine oxidase B (MAO-B) in the human brain using high-resolution positron emission tomography (PET). Seven healthy subjects underwent two separate 90- minute PET scans after an intravenous injection of [¹¹C]SL25.1188. Complementary arterial blood sampling was acquired. Radioactivity was quickly eliminated from plasma with 80% of parent compound remaining at 90 minutes. Metabolites were more polar than the parent compound. Time-activity curves showed high brain uptake, early peak and washout rate consistent with known regional MAO-B concentration. A two-tissue compartment model (2-TCM) provided better fits to the data than a 1-TCM. Measurement of total distribution volume (V_T) showed very good identifiability (based on coefficient of variation (COV)) for all regions of interest (ROIs) (COV(V_T)<8%), low between-subject variability (∼20%), and quick temporal convergence (within 5% of final value at 45 minutes). Logan graphical method produces very good estimation of V_T. Regional V_T highly correlated with previous postmortem report of MAO-B level (r²=⩾0.9). Specific binding would account from 70% to 90% of V_T. Hence, V_T measurement of [¹¹C]SL25.1¹88 PET is an excellent estimation of MAO-B concentration.     

Measurement of density and affinity for dopamine D2 receptors by a single positron emission tomography scan with multiple injections of [11C]raclopride

Positron emission tomography (PET) with [¹¹C]raclopride has been used to investigate the density (B_max) and affinity (K_d) of dopamine D₂ receptors related to several neurological and psychiatric disorders. However, in assessing the B_max and K_d, multiple PET scans are necessary under variable specific activities of administered [¹¹C]raclopride, resulting in a long study period and unexpected physiological variations. In this paper, we have developed a method of multiple-injection graphical analysis (MI-GA) that provides the B_max and K_d values from a single PET scan with three sequential injections of [¹¹C]raclopride, and we validated the proposed method by performing numerous simulations and PET studies on monkeys. In the simulations, the three-injection protocol was designed according to prior knowledge of the receptor kinetics, and the errors of B_max and K_d estimated by MI-GA were analyzed. Simulations showed that our method could support the calculation of B_max and K_d, despite a slight overestimation compared with the true magnitudes. In monkey studies, we could calculate the B_max and K_d of diseased or normal striatum in a 150 mins scan with the three-injection protocol of [¹¹C]raclopride. Estimated B_max and K_d values of D₂ receptors in normal or partially dopamine-depleted striatum were comparable to the previously reported values.     

In vivo quantification of monoamine oxidase A in baboon brain: a PET study using [11C]befloxatone and the multi-injection approach

[¹¹C]befloxatone is a high-affinity, reversible, and selective radioligand for the in vivo visualization of the monoamine oxidase A (MAO-A) binding sites using positron emission tomography (PET). The multi-injection approach was used to study in baboons the interactions between the MAO-A binding sites and [¹¹C]befloxatone. The model included four compartments and seven parameters. The arterial plasma concentration, corrected for metabolites, was used as input function. The experimental protocol—three injections of labeled and/or unlabeled befloxatone—allowed the evaluation of all the model parameters from a single PET experiment. In particular, the brain regional concentrations of the MAO-A binding sites (B′_max) and the apparent in vivo befloxatone affinity (K_d) were estimated in vivo for the first time. A high binding site density was found in almost all the brain structures (170±39 and 194±26 pmol/mL in the frontal cortex and striata, respectively, n=5). The cerebellum presented the lowest binding site density (66±13 pmol/mL). Apparent affinity was found to be similar in all structures (K_dV_R=6.4±1.5 nmol/L). This study is the first PET-based estimation of the B_max of an enzyme.     

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.     

Increased dopamine D2/D3 receptor binding after recovery from anorexia nervosa measured by positron emission tomography and [11c]raclopride.

BACKGROUND: Several lines of evidence support the possibility that disturbances of dopamine (DA) function could contribute to alterations of weight, feeding, motor activity, and reward in anorexia nervosa (AN). METHODS: To assess possibly trait-related disturbances but avoid confounding effects of malnutrition, 10 women who were recovered from AN (REC AN) were compared with 12 healthy control women (CW). Positron emission tomography with [(11)C]raclopride was used to assess DA D2/D3 receptor binding. RESULTS: The women who were recovered from AN had significantly higher [(11)C]raclopride binding potential in the antero-ventral striatum than CW. For REC AN, [(11)C]raclopride binding potential was positively related to harm avoidance in the dorsal caudate and dorsal putamen. CONCLUSIONS: These data lend support for the possibility that decreased intrasynaptic DA concentration or increased D2/D3 receptor density or affinity is associated with AN and might contribute to the characteristic harm avoidance or increased physical activity found in AN. Most intriguing is the possibility that individuals with AN might have a DA related disturbance of reward mechanisms contributing to altered hedonics of feeding behavior and their ascetic, anhedonic temperament.     

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.     

Parametric mapping of [18F]fluoromisonidazole positron emission tomography using basis functions

In this study, we show a basis function method (BAFPIC) for voxelwise calculation of kinetic parameters (K₁, k₂, k₃, K_i) and blood volume using an irreversible two-tissue compartment model. BAFPIC was applied to rat ischaemic stroke micro-positron emission tomography data acquired with the hypoxia tracer [¹⁸F]fluoromisonidazole because irreversible two-tissue compartmental modelling provided good fits to data from both hypoxic and normoxic tissues. Simulated data show that BAFPIC produces kinetic parameters with significantly lower variability and bias than nonlinear least squares (NLLS) modelling in hypoxic tissue. The advantage of BAFPIC over NLLS is less pronounced in normoxic tissue. K_i determined from BAFPIC has lower variability than that from the Patlak–Gjedde graphical analysis (PGA) by up to 40% and lower bias, except for normoxic tissue at mid-high noise levels. Consistent with the simulation results, BAFPIC parametric maps of real data suffer less noise-induced variability than do NLLS and PGA. Delineation of hypoxia on BAFPIC k₃ maps is aided by low variability in normoxic tissue, which matches that in K_i maps. BAFPIC produces K_i values that correlate well with those from PGA (r²=0.93 to 0.97; slope 0.99 to 1.05, absolute intercept <0.00002 mL/g per min). BAFPIC is a computationally efficient method of determining parametric maps with low bias and variance.     

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.     

Increase in thalamic binding of [C]PE2I in patients with schizophrenia: A positron emission tomography study of dopamine transporter

Previous in vivo imaging studies reported no difference in dopamine transporter (DAT) bindings in the striatum between control subjects and patients with schizophrenia. However, as the signals of radioligands with moderate affinity were insufficient for allowing the evaluation of small amounts of DAT, DAT binding in extrastriatal regions has not been determined. Positron emission tomography scanning using [¹¹C]PE2I was performed on eight patients with schizophrenia and twelve normal control subjects. Binding potential (BP_ND) for DAT in the caudate, putamen, thalamus and substantia nigra was calculated, using the cerebellum as reference region. In patients with schizophrenia, clinical symptoms were evaluated by Positive and Negative Syndrome Scale (PANSS). BP_ND in the thalamus of patients with schizophrenia was significantly higher than in control subjects (P = 0.044). In patients with schizophrenia, there were significantly positive correlations between BP_ND in the thalamus and total (r = 0.75), positive (r = 0.78) and negative PANSS scores (r = 0.82). Altered DAT in the thalamus might be related to the pathophysiology and clinical symptoms of schizophrenia.     

Characterization of in vivo pharmacokinetic properties of the dopamine D1 receptor agonist DAR-0100A in nonhuman primates using PET with [11C] NNC112 and [11C] raclopride

DAR-0100A, the active enantiomer of dihydrexidine, is a potent dopamine D1 agonist under investigation for treatment of cognitive impairment and negative symptoms of schizophrenia. We measured the dose–occupancy relationship for DAR-0100A at D1 receptors using positron emission tomography (PET) imaging in baboons with [¹¹C] NNC112 and its binding to D2 with [¹¹C] raclopride. Two baboons were scanned with [¹¹C] NNC112 at baseline and after three different doses of DAR-0100A. Two baboons were scanned with [¹¹C] raclopride at baseline and after one dose of DAR-0100A. Occupancy (ΔBP_ND) was computed in the striatum and cortex. A clear relationship was observed between plasma concentration of DAR-0100A and ΔBP_ND. ΔBP_ND was larger in the striatum than in the cortex, consistent with reports showing that 25% of [¹¹C] NNC112 BP_ND in the cortex is attributed to 5-HT_2A. Plasma EC₅₀ estimates ranged from 150 to 550 ng/mL according to the constraints on the model. There was no detectable effect of DAR-0100A on [¹¹C] raclopride BP_ND. These data suggest that at doses likely to be administered to patients, occupancy will not be detectable with [¹¹C] NNC112 PET and binding of DAR-0100A to D2 will be negligible. This is the first demonstration with PET of a significant occupancy by a full D1 agonist in vivo.     

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.     

In vivo and in vitro validation of reference tissue models for the mGluR5 ligand [11C]ABP688

The primary objective of this study was to verify the suitability of reference tissue-based quantification methods of the metabotropic glutamate receptor type 5 (mGluR₅) with [¹¹C]ABP688. This study presents in vivo (Positron Emission Tomography (PET)) and in vitro (autoradiography) measurements of mGluR₅ densities in the same rats and evaluates both noninvasive and blood-dependent pharmacokinetic models for the quantification of [¹¹C]ABP688 binding. Eleven rats underwent [¹¹C]ABP688 PET scans. In five animals, baseline scans were compared with blockade experiments with the antagonist 1,2-methyl-6-(phenylethynyl)-pyridine (MPEP), and arterial blood samples were drawn and corrected for metabolites. Afterward, saturation-binding autoradiography was performed. Blocking with MPEP resulted in an average decrease of the total distribution volume (V_T) between 43% and 58% (thalamus and caudate-putamen, respectively) but had no significant effect on cerebellar V_T (mean reduction: −0.01%). Comparing binding potential (BP_ND) based on the V_T with noninvasively determined BP_ND revealed an average negative bias of 0.7% in the caudate-putamen and an average positive bias of 3.1% in the low-binding regions. Scan duration of 50 minutes is required. The cerebellum is a suitable reference region for the quantification of mGluR₅ availability as measured with [¹¹C]ABP688 PET in rats. Blood-based and reference region-based PET quantification shows a significant linear relationship to autoradiographic determinations.     

Binding of the synaptic vesicle radiotracer [11C]UCB-J is unchanged during functional brain activation using a visual stimulation task

The positron emission tomography radioligand [¹¹C]UCB-J binds to synaptic vesicle glycoprotein 2 A (SV2A), a regulator of vesicle release. Increased neuronal firing could potentially affect tracer concentrations if binding site availability is altered during vesicle exocytosis. This study assessed whether physiological brain activation induces changes in [¹¹C]UCB-J tissue influx (K₁), volume of distribution (V_T), or binding potential (BP_ND). Healthy volunteers (n = 7) underwent 60-min [¹¹C]UCB-J PET scans at baseline and during intermittent presentation of 8-Hz checkerboard visual stimulation. Sensitivity to intermittent changes in kinetic parameters was assessed in simulations, and visual stimulation was repeated using functional magnetic resonance imaging to characterize neural responses. V_T  and K₁ were determined using the one-tissue compartment model and BP_ND using the simplified reference tissue model. In primary visual cortex, K₁ increased 34.3 ± 15.5% (p = 0.001) during stimulation, with no change in other regions (ps > 0.12). K₁ change was correlated with fMRI BOLD response (r = 0.77, p = 0.043). There was no change in V_T (−3.9 ± 8.8%, p = 0.33) or BP_ND (−0.2 ± 9.6%, p = 0.94) in visual cortex nor other regions (ps > 0.19). Therefore, despite robust increases in regional tracer influx due to blood flow increases, binding measures were unchanged during stimulation. [¹¹C]UCB-J V_T and BP_ND are likely to be stable in vivo measures of synaptic density.     

Determination of [11C]PBR28 binding potential in vivo: a first human TSPO blocking study

Positron emission tomography (PET) targeting the 18 kDa translocator protein (TSPO) is used to quantify neuroinflammation. Translocator protein is expressed throughout the brain, and therefore a classical reference region approach cannot be used to estimate binding potential (BP_ND). Here, we used blockade of the TSPO radioligand [¹¹C]PBR28 with the TSPO ligand XBD173, to determine the non-displaceable volume of distribution (V_ND), and hence estimate the BP_ND. A total of 26 healthy volunteers, 16 high-affinity binders (HABs) and 10 mixed affinity binders (MABs) underwent a [¹¹C]PBR28 PET scan with arterial sampling. Six of the HABs received oral XBD173 (10 to 90 mg), 2 hours before a repeat scan. In XBD173-dosed subjects, V_ND was estimated via the occupancy plot. Values of BP_ND for all subjects were calculated using this V_ND estimate. Total volume of distribution (V_T) of MABs (2.94±0.31) was lower than V_T of HABs (4.33±0.29) (P<0.005). There was dose-dependent occupancy of TSPO by XBD173 (ED50=0.34±0.13 mg/kg). The occupancy plot provided a V_ND estimate of 1.98 (1.69, 2.26). Based on these V_ND estimates, BP_ND for HABs is approximately twice that of MABs, consistent with predictions from in vitro data. Our estimates of [¹¹C]PBR28 V_ND and hence BP_ND in the healthy human brain are consistent with in vitro predictions. XBD173 blockade provides a practical means of estimating V_ND for TSPO targeting radioligands.     

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.     

In vivo serotonin-sensitive binding of [11C]CUMI-101: a serotonin 1A receptor agonist positron emission tomography radiotracer

Positron emission tomography studies of 5-hydroxytryptamine (5-HT)_1A receptors have hitherto been limited to antagonist radiotracers. Antagonists do not distinguish high/low-affinity conformations of G protein-coupled receptors and are less likely to be sensitive to intrasynaptic serotonin levels. We developed a novel 5-HT_1A agonist radiotracer [¹¹C]CUMI-101. This study evaluates the sensitivity of [¹¹C]CUMI-101 binding to increases in intrasynaptic serotonin induced by intravenous citalopram and fenfluramine. Two Papio anubis were scanned, using [¹¹C]CUMI-101 intravenous bolus of 4.5±1.5 mCi. Binding potential (BP_F=B_avail/K_D) was measured before (n=10) and 20 minutes after elevation of intrasynaptic serotonin by intravenous citalopram (2 mg/kg, n=3; 4 mg/kg, n=3) and fenfluramine (2.5 mg/kg, n=3) using a metabolite-corrected arterial input function. Occupancy was also estimated by the Lassen graphical approach. Both citalopram and fenfluramine effects were significant for BP_F (P=0.031, P=0.049, respectively). The Lassen approach estimated 15.0, 30.4, and 23.7% average occupancy after citalopram 2 mg/kg, 4 mg/kg, and fenfluramine 2.5 mg/kg, respectively. [¹¹C]CUMI-101 binding is sensitive to a large increase in intrasynaptic serotonin in response to robust pharmacological challenges. These modest changes in BP_F may make it unlikely that this ligand will detect changes in intrasynaptic 5-HT under physiologic conditions; future work will focus on evaluating its utility in measuring the responsiveness of the 5-HT system to pharmacological challenges.