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The highly diverse serotonergic system with at least 16 different receptor subtypes is implicated in the pathophysiology of most neuropsychiatric disorders including affective and anxiety disorders, obsessive compulsive disorder, post-traumatic stress disorder, eating disorders, sleep disturbance, attention deficit/hyperactivity disorder, drug addiction, suicidal behavior, schizophrenia, Alzheimer, etc. Alterations of the interplay between various pre- and postsynaptic receptor subtypes might be involved in the pathogenesis of these disorders. However, there is a lack of comprehensive in vivo values using standardized procedures. In the current PET study we quantified 3 receptor subtypes, including the major inhibitory (5‐HT1A and 5‐HT1B) and excitatory (5‐HT2A) receptors, and the transporter (5‐HTT) in the brain of healthy human subjects to provide a database of standard values. PET scans were performed on 95 healthy subjects (age=28.0±6.9years; 59% males) using the selective radioligands [carbonyl-11C]WAY-100635, [11C]P943, [18F]altanserin and [11C]DASB, respectively. A standard template in MNI stereotactic space served for region of interest delineation. This template follows two anatomical parcellation schemes: 1) Brodmann areas including 41 regions and 2) AAL (automated anatomical labeling) including 52 regions. Standard values (mean, SD, and range) for each receptor and region are presented. Mean cortical and subcortical binding potential (BP) values were in good agreement with previously published human in vivo and post-mortem data. By means of linear equations, PET binding potentials were translated to post-mortem binding (provided in pmol/g), yielding 5.89pmol/g (5‐HT1A), 23.5pmol/g (5‐HT1B), 31.44pmol/g (5‐HT2A), and 11.33pmol/g (5‐HTT) being equivalent to the BP of 1, respectively. Furthermore, we computed individual voxel-wise maps with BP values and generated average tracer-specific whole-brain binding maps. This knowledge might improve our interpretation of the alterations taking place in the serotonergic system during neuropsychiatric disorders. ► In vivo quantification of 5-HT 1A, 1B, 2A and 5-HTT in 95 healthy subjects ► PET radioligands [carbonyl-11C]WAY-100635, [11C]P943, [18F]altanserin and [11C]DASB ► Using a standard template in MNI space, a total of 93 ROIs were analyzed. ► The mean, SD and range of binding potentials (BPs) are provided. ► Using linear equations, in vivo PET BP was compared to post-mortem protein density.

Brain cannabinoid 1 receptors (CB1Rs) contribute importantly to the regulation of autonomic tone, appetite, mood and cognition. Inconsistent results have been reported from positron emission tomography (PET) studies using different radioligands to examine relationships between age, gender and body mass index (BMI) and CB1R availability in healthy individuals. In this study, we examined these variables in 58 healthy individuals (age range: 18–55 years; 44 male; BMI=27.01±5.56), the largest cohort of subjects studied to date using the CB1R PET ligand [11C]OMAR. There was a significant decline in CB1R availability (VT) with age in the pallidum, cerebellum and posterior cingulate. Adjusting for BMI, age-related decline in VT remained significant in the posterior cingulate among males, and in the cerebellum among women. CB1R availability was higher in women compared to men in the thalamus, pallidum and posterior cingulate. Adjusting for age, CB1R availability negatively correlated with BMI in women but not men. These findings differ from those reported using [11C]OMAR and other radioligands such as [18F]FMPEP-d2 and [18F]MK-9470. Although reasons for these seemingly divergent findings are unclear, the choice of PET radioligand and range of BMI in the current dataset may contribute to the observed differences. This study highlights the need for cross-validation studies using both [11C]OMAR and [18F]FMPEP-d2 within the same cohort of subjects.

Parkinson’s disease (PD) is the fastest growing neurodegenerative disease, but at present there is no cure, nor any disease-modifying treatments. Synaptic biomarkers from in vivo imaging have shown promise in imaging loss of synapses in PD and other neurodegenerative disorders. Here, we provide new clinical insights from a cross-sectional, high-resolution positron emission tomography (PET) study of 30 PD individuals and 30 age- and sex-matched healthy controls (HC) with the radiotracer [ 11 C]UCB-J, which binds to synaptic vesicle glycoprotein 2A (SV2A), and is therefore, a biomarker of synaptic density in the living brain. We also examined a measure of relative brain perfusion from the early part of the same PET scan. Our results provide evidence for synaptic density loss in the substantia nigra that had been previously reported, but also extend this to other early-Braak stage regions known to be affected in PD (brainstem, caudate, olfactory cortex). Importantly, we also found a direct association between synaptic density loss in the nigra and severity of symptoms in patients. A greater extent and wider distribution of synaptic density loss in PD patients with longer illness duration suggests that [ 11 C]UCB-J PET can be used to measure synapse loss with disease progression. We also demonstrate lower brain perfusion in PD vs. HC groups, with a greater extent of abnormalities in those with longer duration of illness, suggesting that [ 11 C]UCB-J PET can simultaneously provide information on changes in brain perfusion. These results implicate synaptic imaging as a useful PD biomarker for future disease-modifying interventions.

BackgroundAntiepileptic drugs, levetiracetam (LEV) and brivaracetam (BRV), bind to synaptic vesicle glycoprotein 2A (SV2A). In their anti-seizure activity, speed of brain entry may be an important factor. BRV showed faster entry into the human and non-human primate brain, based on more rapid displacement of SV2A tracer 11C-UCB-J. To extract additional information from previous human studies, we developed a nonlinear model that accounted for drug entry into the brain and binding to SV2A using brain 11C-UCB-J positron emission tomography (PET) data and the time-varying plasma drug concentration, to assess the kinetic parameter K1 (brain entry rate) of the drugs.MethodDisplacement (LEV or BRV p.i. 60 min post-tracer injection) and post-dose scans were conducted in five healthy subjects. Blood samples were collected for measurement of drug concentration and the tracer arterial input function. Fitting of nonlinear differential equations was applied simultaneously to time-activity curves (TACs) from displacement and post-dose scans to estimate 5 parameters: K1 (drug), K1(11C-UCB-J, displacement), K1(11C-UCB-J, post-dose), free fraction of 11C-UCB-J in brain (fND(11C-UCB-J)), and distribution volume of 11C-UCB-J (VT(UCB-J)). Other parameters (KD(drug), KD(11C-UCB-J), fP(drug), fP(11C-UCB-J, displacement), fP(11C-UCB-J, post-dose), fND(drug), koff(drug), koff(11C-UCB-J)) were fixed to literature or measured values.ResultsThe proposed model described well the TACs in all subjects; however, estimates of drug K1 were unstable in comparison with 11C-UCB-J K1 estimation. To provide a conservative estimate of the relative speed of brain entry for BRV vs. LEV, we determined a lower bound on the ratio BRV K1/LEV K1, by finding the lowest BRV K1 or highest LEV K1 that were statistically consistent with the data. Specifically, we used the F test to compare the residual sum of squares with fixed BRV K1 to that with floating BRV K1 to obtain the lowest possible BRV K1; the same analysis was performed to find the highest LEV K1. The lower bound of the ratio BRV K1/LEV K1 was ~ 7.ConclusionsUnder appropriate conditions, this advanced nonlinear model can directly estimate entry rates of drugs into tissue by analysis of PET TACs. Using a conservative statistical cutoff, BRV enters the brain at least sevenfold faster than LEV.

Several lines of evidence suggest that altered serotonin (5-HT) function persists after recovery from anorexia nervosa (AN) and bulimia nervosa (BN). We compared 11 subjects who recovered (>1 year normal weight, regular menstrual cycles, no binging or purging) from restricting-type AN (REC RAN), 7 who recovered from bulimia-type AN (REC BAN), 9 who recovered from BN (REC BN), and 10 healthy control women (CW). Positron emission tomography (PET) imaging with [11C]McN5652 was used to assess the 5-HT transporter (5-HTT). For [11C]McN5652, distribution volume (DV) values were determined using a two-compartment, three-parameter tracer kinetic model, and specific binding was assessed using the binding potential (BP, BP=DVregion of interest/DVcerebellum-1). After correction for multiple comparisons, the four groups showed significant (p<0.05) differences for [11C]McN5652 BP values for the dorsal raphe and antero-ventral striatum (AVS). Post-hoc analysis revealed that REC RAN had significantly increased [11C]McN5652 BP compared to REC BAN in these regions. Divergent 5-HTT activity in subtypes of eating disorder subjects may provide important insights as to why these groups have differences in affective regulation and impulse control.

Several lines of evidence suggest that a disturbance of serotonin neuronal pathways may contribute to the pathogenesis of anorexia nervosa (AN) and bulimia nervosa (BN). This study applied positron emission tomography (PET) to investigate the brain serotonin 2A (5-HT(2A)) receptor, which could contribute to disturbances of appetite and behavior in AN and BN. To avoid the confounding effects of malnutrition, we studied 10 women recovered from bulimia-type AN (REC AN-BN, > 1 year normal weight, regular menstrual cycles, no binging, or purging) compared with 16 healthy control women (CW) using PET imaging and a specific 5-HT(2A) receptor antagonist, [18F]altanserin. REC AN-BN women had significantly reduced [18F]altanserin binding potential relative to CW in the left subgenual cingulate, the left parietal cortex, and the right occipital cortex. [18F]altanserin binding potential was positively related to harm avoidance and negatively related to novelty seeking in cingulate and temporal regions only in REC AN-BN subjects. In addition, REC AN-BN had negative relationships between [18F]altanserin binding potential and drive for thinness in several cortical regions. In conclusion, this study extends research suggesting that altered 5-HT neuronal system activity persists after recovery from bulimia-type AN, particularly in subgenual cingulate regions. Altered 5-HT neurotransmission after recovery also supports the possibility that this may be a trait-related disturbance that contributes to the pathophysiology of eating disorders. It is possible that subgenual cingulate findings are not specific for AN-BN, but may be related to the high incidence of lifetime major depressive disorder diagnosis in these subjects.

OBJECTIVES/SPECIFIC AIMS: The serotonin receptor 6 (5-HT6) is a potential therapeutic target given its distribution in brain regions that are important in depression, anxiety, and cognition. This study sought to investigate the effects of age on 5-HT6 receptor availability using 11C GSK215083, a PET ligand with affinity for 5-HT6 in the striatum and 5-HT2A in the cortex. METHODS/STUDY POPULATION: In total, 28 healthy male subjects (age range: 23–52 years) were scanned with 11C-GSK215083 on the HR+PET scanner. Time-activity curves in regions-of-interest were fitted with multilinear analysis-1 method. Binding potentials (BPND) were calculated using cerebellum as the reference region and corrected for partial volume effects. RESULTS/ANTICIPATED RESULTS: In 5-HT6 rich areas, regional 11C-GSK215083 displayed a negative correlation between BPND and age in the caudate ( r =−0.41, p =0.03) (14% change per decade), and putamen ( r =−0.30, p =0.04) (11% change per decade), but not in the ventral striatum and pallidum. Negative correlation with age was also seen in cortical regions ( r =−0.41, p =0.03) (7% change per decade), consistent with the literature on 5-HT2A availability. DISCUSSION/SIGNIFICANCE OF IMPACT: This is the first in vivo study in humans to examine the effect of age on 5-HT6 receptor availability. The study demonstrated a significant age-related decline in 5-HT6 availability (BPND) in the caudate and putamen.

[18F]SynVesT-1, a positron emission tomography (PET) radiotracer for the synaptic vesicle glycoprotein 2A (SV2A), demonstrates kinetics similar to [11C]UCB-J, with high brain uptake, fast kinetics fitting well with the one-tissue compartment (1TC) model, and excellent test-retest reproducibility. Challenges arise due to the similarity between k2 and [Formula: see text] (efflux rate of the reference region), when applying the simplified reference tissue model (SRTM) and related methods in [11C]UCB-J studies to accurately estimate [Formula: see text]. This study evaluated the suitability of these methods to estimate [18F]SynVesT-1 binding using centrum semiovale (CS) or cerebellum (CER) as reference regions.PURPOSE[18F]SynVesT-1, a positron emission tomography (PET) radiotracer for the synaptic vesicle glycoprotein 2A (SV2A), demonstrates kinetics similar to [11C]UCB-J, with high brain uptake, fast kinetics fitting well with the one-tissue compartment (1TC) model, and excellent test-retest reproducibility. Challenges arise due to the similarity between k2 and [Formula: see text] (efflux rate of the reference region), when applying the simplified reference tissue model (SRTM) and related methods in [11C]UCB-J studies to accurately estimate [Formula: see text]. This study evaluated the suitability of these methods to estimate [18F]SynVesT-1 binding using centrum semiovale (CS) or cerebellum (CER) as reference regions.Seven healthy participants underwent 120-min PET scans on the HRRT scanner with [18F]SynVesT-1. Six participants underwent test and retest scans. Arterial blood sampling and metabolite analysis provided input functions for the 1TC model, serving as the gold standard for kinetic parameters values. SRTM, coupled SRTM (SRTMC) and SRTM2 estimated were applied to estimate [Formula: see text](ref: CS) and DVRCER(ref: CER) values. For SRTM2, the population average of [Formula: see text] was determined from the 1TC model applied to the reference region. Test-retest variability and minimum scan time were also calculated.METHODSeven healthy participants underwent 120-min PET scans on the HRRT scanner with [18F]SynVesT-1. Six participants underwent test and retest scans. Arterial blood sampling and metabolite analysis provided input functions for the 1TC model, serving as the gold standard for kinetic parameters values. SRTM, coupled SRTM (SRTMC) and SRTM2 estimated were applied to estimate [Formula: see text](ref: CS) and DVRCER(ref: CER) values. For SRTM2, the population average of [Formula: see text] was determined from the 1TC model applied to the reference region. Test-retest variability and minimum scan time were also calculated.The 1TC k2 (1/min) values for CS and CER were 0.031 ± 0.004 and 0.021 ± 0.002, respectively. Although SRTMC [Formula: see text] was much higher than 1TC [Formula: see text], SRTMC underestimated BPND(ref: CS) and DVRCER by an average of 3% and 1% across regions, respectively, due to similar bias in k2 and [Formula: see text] estimation. SRTM underestimated BPND(ref: CS) by an average of 3%, but with the CER as reference region, SRTM estimation was unstable and DVRCER underestimation varied by region (mean 10%). Using population average [Formula: see text] values, SRTM2 BPND and DVRCER showed the best agreement with 1TC estimates.RESULTSThe 1TC k2 (1/min) values for CS and CER were 0.031 ± 0.004 and 0.021 ± 0.002, respectively. Although SRTMC [Formula: see text] was much higher than 1TC [Formula: see text], SRTMC underestimated BPND(ref: CS) and DVRCER by an average of 3% and 1% across regions, respectively, due to similar bias in k2 and [Formula: see text] estimation. SRTM underestimated BPND(ref: CS) by an average of 3%, but with the CER as reference region, SRTM estimation was unstable and DVRCER underestimation varied by region (mean 10%). Using population average [Formula: see text] values, SRTM2 BPND and DVRCER showed the best agreement with 1TC estimates.Our findings support the use of population [Formula: see text] value in SRTM2 with [18F]SynVesT-1 for the estimation of [Formula: see text] or DVRCER, regardless of the choice of reference region.CONCLUSIONOur findings support the use of population [Formula: see text] value in SRTM2 with [18F]SynVesT-1 for the estimation of [Formula: see text] or DVRCER, regardless of the choice of reference region.