The applicability of SRTM in [18F]fallypride PET investigations: impact of scan durations

The high-affinity radioligand [¹⁸F]fallypride (FP) is frequently used for quantification of striatal/extrastriatal D_2/3 receptors and the receptor occupancies of antipsychotics (APs). Its 110 minutes half-life allows long scan durations. However, the optimum scan duration is a matter of debate. This investigation focuses on scan-duration-related effects on simplified reference tissue model (SRTM) results and the time point of transient equilibrium in a large sample of dynamic FP positron emission tomography (PET) scans. Fifty drug-free and 50 AP-treated subjects underwent FP-PET scans (180 minutes scan duration). The binding potential (BP_ND) of the putamen, thalamus, and temporal cortex were calculated using the SRTM and the transient equilibrium model. Furthermore, receptor occupancies were calculated for AP-treated patients. Transient equilibrium in the unblocked putamen occurred after 121±29.6 minutes. The transient equilibrium occurred much earlier in the extrastriatal regions or under AP treatment. Stepwise scan shortening caused BP_ND underestimations of 0.58% for the first 10-minute reduction (putamen, SRTM), finally reaching 5.76% after 1 hour scan-time reduction. We observed preferential extrastriatal AP binding irrespective of the analytical method. [¹⁸F]fallypride scan durations of 180 minutes reliably reach equilibrium even in D_2/3-receptor-rich regions. Moderate reductions in FP scan durations only caused small changes to SRTM results even in receptor-rich regions. Apparently, the D_2/3 receptor occupancy results of APs, especially preferential extrastriatal binding observations, are not relevantly biased by inappropriate scan durations.     

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.     

Imaging cortical dopamine D1 receptors using [11C]NNC112 and ketanserin blockade of the 5-HT2A receptors

[¹¹C]NNC112 (8-chloro-7-hydroxy-3-methyl-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-IH-3-benzazepine), a selective positron-emission tomography (PET) ligand for the D₁ receptor (R) over the 5-HT_2A R in vitro, has shown lower selectivity in vivo, hampering measurement of D₁ R in the cortex. [¹¹C]NNC112 PET and intravenous (i.v) ketanserin challenge were used to (1) confirm the previous findings of [¹¹C]NNC112 in vivo D₁ R selectivity, and (2) develop a feasible methodology for imaging cortical D₁ R without contamination by 5-HT_2A R. Seven healthy volunteers underwent [¹¹C]NNC112 PET scans at baseline and after a 5-HT_2A R-blocking dose of ketanserin (0.15 mg/kg, i.v.). Percent BP_ND change between the post-ketanserin and baseline scans was calculated. Irrespective of the quantification method used, ketanserin pretreatment led to significant decrease of BP_ND in the cortical (∼30%) and limbic regions (∼20%) but not in the striatum, which contains a much lower amount of 5-HT_2A R. Therefore, ketanserin allows D₁ R signal to be detected by [¹¹C]NNC112 PET without significant 5-HT_2A R contamination. These data confirm the presence of a significant 5-HT_2A R contribution to cortical [¹¹C]NNC112 signal, and call for caution in the interpretation of published [¹¹C]NNC112 PET findings on cortical D₁ R in humans. In the absence of more selective ligands, [¹¹C]NNC112 PET with ketanserin can be used for cortical D₁ R imaging in vivo.     

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.     

Quantification of [11C]yohimbine binding to α2 adrenoceptors in rat brain in vivo

We quantified the binding potentials (BP_ND) of [¹¹C]yohimbine binding in rat brain to alpha-2 adrenoceptors to evaluate [¹¹C]yohimbine as an in vivo marker of noradrenergic neurotransmission and to examine its sensitivity to the level of noradrenaline. Dual [¹¹C]yohimbine dynamic positron emission tomography (PET) recordings were applied to five Sprague Dawley rats at baseline, followed by acute amphetamine administration (2 mg/kg) to induce elevation of the endogenous level of noradrenaline. The volume of distribution (V_T) of [¹¹C]yohimbine was obtained using Logan plot with arterial plasma input. Because alpha-2 adrenoceptors are distributed throughout the brain, the estimation of the BP_ND is complicated by the absence of an anatomic region of no displaceable binding. We used the Inhibition plot to acquire the reference volume, V_ND, from which we calculated the BP_ND. Acute pharmacological challenge with amphetamine induced a significant decline of [¹¹C]yohimbine BP_ND of ~38% in all volumes of interest. The BP_ND was greatest in the thalamus and striatum, followed in descending order by, frontal cortex, pons, and cerebellum. The experimental data demonstrate that [¹¹C]yohimbine binding is sensitive to a challenge known to increase the extracellular level of noradrenaline, which can benefit future PET investigations of pathologic conditions related to disrupted noradrenergic neurotransmission.     

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.     

Noninvasive quantification of metabotropic glutamate receptor type 1 with [11C]ITDM: a small-animal PET study

Because of its role in multiple central nervous system (CNS) pathways, metabotropic glutamate receptor type 1 (mGluR1) is a crucial target in the development of pharmaceuticals for CNS disorders. N-[4-[6-(isopropylamino)-pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methyl-4-[¹¹C]-methylbenzamide ([¹¹C]ITDM) was recently developed as a positron emission tomography (PET) ligand for mGluR1. To devise a method for measurement of the binding potential (BP_ND) of [¹¹C]ITDM to mGluR1, reference tissue methods aimed at replacing measurement of the arterial input function are desirable. In this study, we evaluated a noninvasive quantification method of mGluR1 with [¹¹C]ITDM, demonstrating its accuracy using Huntington disease model R6/2 mice. The BP_ND measurements based on the Logan reference (Logan Ref) method have closely approximated that based on the arterial input method. We performed PET analysis with Logan Ref to assess its accuracy in quantifying the decline of mGluR1 expression in R6/2 mice. Significant decreases in BP_ND values in R6/2 mice were detected in cerebellum, thalamus, striatum, and cingulate cortex. We compared autoradiographs of R6/2 mouse brain sections with immunohistochemical images, and found a close correlation between changes in radioactive signal intensity and degree of mGluR1 expression. In conclusion, [¹¹C]ITDM-PET is a promising tool for in vivo quantification of mGluR1 expression.     

An open‐label positron emission tomography study to evaluate serotonin transporter occupancy following escalating dosing regimens of (R)‐(–)‐O‐desmethylvenlafaxine and racemic O‐desmethylvenlafaxine

SEP‐227162 [R(–)‐O‐desmethylvenlafaxine] is an enantiomer of the venlafaxine metabolite O‐desmethylvenlafaxine (ODV, Pristiq?, Wyeth). This study compared the serotonin transporter (SERT) occupancy achieved by SEP‐227162 and ODV, at daily doses of 25, 50, 100, and 150 mg using [¹¹C]DASB positron emission tomography (PET). Sixteen healthy male subjects participated in one of four dose groups (N = 4 per group) during which they were administered two doses of the study drug (SEP‐227162 or ODV). For each study drug, total daily doses of 25, 50, 100, and150 mg were studied. Subjects underwent three PET scans with [¹¹C]DASB. A baseline, off‐medication, scan was performed prior to dosing and a [¹¹C]DASB PET scan was performed after 72 hr at each dose level. [¹¹C]DASB binding potential (BP_ND) was calculated using the simplified reference tissue method. SERT occupancy was calculated as the change in BP_ND (ΔBP_ND) from baseline scan to the on‐medication scan relative to the baseline BP_ND value. SEP‐227162 and ODV significantly reduced regional distribution volumes and region BP_ND values in a dose‐dependent manner. Across all doses ODV produced significantly greater SERT occupancy than SEP‐227162 (ANOVA F = 21.8, df = 1,23, p < .001). The total daily dose required to provide 50% SERT occupancy was 24.8 mg for SEP‐227162 and 14.4 mg for ODV. In vitro data suggests a ratio of 3.3:1 for binding at human SERT for SEP‐227162 relative to ODV. Our study suggests a ratio of 1.7:1, highlighting the value of in vivo imaging in the drug development process.     

Kinetics and 28-day test–retest repeatability and reproducibility of [11C]UCB-J PET brain imaging

[¹¹C]UCB-J is a novel radioligand that binds to synaptic vesicle glycoprotein 2A (SV2A). The main objective of this study was to determine the 28-day test–retest repeatability (TRT) of quantitative [¹¹C]UCB-J brain positron emission tomography (PET) imaging in Alzheimer’s disease (AD) patients and healthy controls (HCs). Nine HCs and eight AD patients underwent two 60 min dynamic [¹¹C]UCB-J PET scans with arterial sampling with an interval of 28 days. The optimal tracer kinetic model was assessed using the Akaike criteria (AIC). Micro-/macro-parameters such as tracer delivery (K₁) and volume of distribution (V_T) were estimated using the optimal model. Data were also analysed for simplified reference tissue model (SRTM) with centrum semi-ovale (white matter) as reference region. Based on AIC, both 1T2k_V_B and 2T4k_V_B described the [¹¹C]UCB-J kinetics equally well. Analysis showed that whole-brain grey matter TRT for V_T, DVR and SRTM BP_ND were –2.2% ± 8.5, 0.4% ± 12.0 and –8.0% ± 10.2, averaged over all subjects. [¹¹C]UCB-J kinetics can be well described by a 1T2k_V_B model, and a 60 min scan duration was sufficient to obtain reliable estimates for both plasma input and reference tissue models. TRT for V_T, DVR and BP_ND was <15% (1SD) averaged over all subjects and indicates adequate quantitative repeatability of [¹¹C]UCB-J PET.     

Quantification of aromatase binding in the female human brain using [11C]cetrozole positron emission tomography

Aromatase, the enzyme that in the brain converts testosterone and androstenedione to estradiol and estrone, respectively, is a putative key factor in psychoneuroendocrinology. In vivo assessment of aromatase was performed to evaluate tracer kinetic models and optimal scan duration, for quantitative analysis of the aromatase positron emission tomography (PET) ligand [¹¹C]cetrozole. Anatomical magnetic resonance and 90-min dynamic [¹¹C]cetrozole PET-CT scans were performed on healthy women. Volume of interest (VOI)-based analyses with a plasma-input function were performed using the single-tissue and two-tissue (2TCM) reversible compartment models and plasma-input Logan analysis. Additionally, the simplified reference tissue model (SRTM), Logan reference tissue model (LRTM), and standardized uptake volume ratio model, with cerebellum as reference region, were evaluated. Parametric images were generated and regionally averaged voxel values were compared with VOI-based analyses of the reference tissue models. The optimal reference model was used for evaluation of a decreased scan duration. Differences between the plasma-input- and reference tissue-based methods and comparisons between scan durations were assessed by linear regression. The [¹¹C]cetrozole time–activity curves were best described by the 2TCM. SRTM nondisplaceable binding potential (BP_ND), with cerebellum as reference region, can be used to estimate [¹¹C]cetrozole binding and generated robust and quantitatively accurate results for a reduced scan duration of 60 min. Receptor parametric mapping, a basis function implementation of SRTM, as well as LRTM, produced quantitatively accurate parametric images, showing BP_ND at the voxel level. As PET tracer, [¹¹C]cetrozole can be employed for relatively short brain scans to measure aromatase binding using a reference tissue-based approach.     

Test-retest stability of cerebral mGluR₅ quantification using [¹¹C]ABP688 and positron emission tomography in rats

This study evaluates the reproducibility of the quantification of metabotropic glutamate receptor type 5 (mGluR₅) densities in rats using the PET radiotracer [¹¹C]ABP688 and pharmacokinetic models that are based on an input function, which is derived from a reference tissue. Seven rats underwent dynamic PET scans (60 min) after bolus injection of [¹¹C]ABP688. Kinetic analyses included: binding potential (BP_ND) determined by calculating (a) the simplified reference tissue model (SRTM) and (b) its two‐steps simplified version (SRTM2); (c) multilinear reference tissue model (MRTM) and (d) its 2‐parameter version (MRTM2); (e) noninvasive graphical analysis (NIGA). Parametric images were generated representing BP_ND by the MRTM2 model. BP_ND determinations were reproducible with low to acceptable variability ranging from 5 to 10% and reproducibility scores (intraclass correlation coefficient) between 0.51 and 0.88. The pharmacokinetic model that showed lowest overall variability was the SRTM. In contrast, the use of the NIGA was associated with significantly lower reproducibility scores. Comparison of parametric images revealed no significant bias between test and retest measurements and is therefore suitable to compare groups at voxel levels. In conclusion, our results suggest that noninvasive quantification of [¹¹C]ABP688 imaging is reproducible and reliable for PET studies of the cerebral mGluR₅ in rats. Synapse, 2012. © 2012 Wiley Periodicals, Inc.     

Test–retest variability of [11C]ABP688 estimates of metabotropic glutamate receptor subtype 5 availability in humans

[¹¹C]ABP688 is a positron emission tomography (PET) radioligand that binds selectively to metabotropic glutamate type 5 receptors (mGluR5). The use of this tracer has identified receptor binding changes in clinical populations, and has been informative in drug occupancy studies. However, previous studies have found significant increases in [¹¹C]ABP688 binding in the later scan of same‐day comparisons, and estimates of test‐retest reliability under consistent scanning conditions are not available. The objective of this study was to assess the variability of [¹¹C]ABP688 binding in healthy people in scans performed at the same time of day. Two [¹¹C]ABP688 scans were acquired in eight healthy volunteers (6 women, 2 men) using a high‐resolution research tomograph (HRRT). Scans were acquired 3 weeks apart with start times between 10:00am and 1:30pm. Mean mGluR5 binding potential (BP_ND) values were calculated across cortical, striatal and limbic brain regions. Participants reported on subjective mood state after each scan and blood samples were drawn for cortisol analysis. No significant change in BP_ND between scans was observed. Variability in BP_ND values of 11–21% was observed across regions, with the greatest change in the hippocampus and amygdala. Reliability was low to moderate. BP_ND was not statistically related to scan start time, subjective anxiety, serum cortisol levels, or menstrual phase in women. Overall, [¹¹C]ABP688 BP_ND estimates show moderate variability in healthy people. Reliability is fair in cortical and striatal regions, and lower in limbic regions. Future research using this ligand should account for this in study design and analysis.     

Brain translocator protein occupancy by ONO‐2952 in healthy adults: A Phase 1 PET study using [11C]PBR28

ONO‐2952, a novel antagonist of translocator protein 18 kDa (TSPO), binds with high affinity to TSPO in rat brain and human tumor cell line membrane preparations. This study used the TSPO‐specific PET radioligand [¹¹ C]PBR28 to confirm binding of ONO‐2952 to brain TSPO in human subjects, and evaluate brain TSPO occupancy and its relationship with ONO‐2952 plasma concentration. Sixteen healthy subjects received a single oral dose of 200, 60, 20, or 6 mg ONO‐2952 (n = 4 per dose). Two PET scans with [¹¹ C]PBR28 were conducted ≤7 days apart: at baseline and 24 h after ONO‐2952 administration. [¹¹ C]PBR28 regional distribution volume (V_T) was derived with kinetic modeling using the arterial input function and a two tissue compartment model. Nonspecific binding (V_ND) was obtained on an individual basis for each subject using linear regression as the x‐intercept of the Lassen plot. The binding potential relative to V_ND (BP_ND) was derived as the difference between V_T in the ROI (V_T ROI) and V_ND, normalized to V_ND; BP_ND = (V_T ROI – V_ND)/V_ND. TSPO occupancy was calculated as the change in BP_ND (ΔBP_ND) from individual's baseline scan to the on‐medication scan to the baseline BP_ND value. TSPO occupancy by ONO‐2952 was dose dependent between 20–200 mg, approaching saturation at 200 mg both in the whole brain and in 15 anatomic regions of interest (ROI). Estimated K_i values ranged from 24.1 to 72.2 nM. This open‐label, single‐center, single‐dose study demonstrated engagement of ONO‐2952 to brain TSPO. The relationship between pharmacokinetics and TSPO occupancy observed in this study support the hypothesis that ONO‐2952 could potentially modulate neurosteroid production by binding to brain TSPO.     

Dopamine D2/3 receptor occupancy of apomorphine in the nonhuman primate brain—A comparative PET study with [11C]raclopride and [11C]MNPA

Binding studies in vitro have demonstrated that the dopamine D₂ receptor may exist in two affinity states for agonists. The high affinity state is thought to represent the functional state of the receptor and proportions might alter during disease. In vitro studies further indicate that agonists induce measurable D₂ receptor occupancy at clinically relevant concentrations but only when measured at the high affinity state. Recently developed PET‐radioligands, such as [¹¹C]MNPA, have now made it possible to directly study agonist binding in vivo. The aim of this study was to compare the inhibition by apomorphine of agonist and antagonist radioligand binding to D_2/3 receptors in vivo. A total of 36 PET measurements were performed with the D_2/3 antagonist [¹¹C]raclopride or the D_2/3 agonist [¹¹C]MNPA in two cynomolgus monkeys. On each study day, a baseline measurement was followed by two consecutive pretreatment studies with rising doses of apomorphine (0.01, 0.05, 0.15, 0.5, 1.0, and 3.0 mg/kg). Binding potential (BP_ND) values were calculated for the striatum with cerebellum as reference region. Apomorphine inhibited [¹¹C]raclopride and [¹¹C]MNPA binding in a dose‐dependent manner and to a similar extent. ID₅₀ and K_i values were 0.26 mg/kg and 29 ng/ml for [¹¹C]raclopride and 0.50 mg/kg and 31 ng/ml for [¹¹C]MNPA. The present observations do not support the existence of two affinity states in vivo. It might thus be speculated that all D_2/3 receptors are in the high affinity state at in vivo conditions. Synapse 63:378–389, 2009. © 2009 Wiley‐Liss, Inc.     

Similar striatal D2/D3 dopamine receptor availability in adults with Tourette syndrome compared with healthy controls: A [11C]‐(+)‐PHNO and [11C]raclopride positron emission tomography imaging study

Pharmacological and anatomical evidence implicates striatal dopamine receptors in Tourette syndrome (TS). Nevertheless, results of positron emission tomography (PET) studies of the dopamine system in TS have been inconsistent. We investigated striatal D2/3 dopamine receptors in TS using the radioligands [¹¹C]raclopride and [¹¹C]‐(+)‐PHNO, an agonist that binds preferentially to D3 receptors, thus allowing higher sensitivity and measurement of receptors in a high affinity state. Eleven adults with TS and 11 matched healthy control (HC) participants underwent [¹¹C]raclopride and [¹¹C]‐(+)‐PHNO PET scans. General linear model was used for voxelwise contrasts of striatal binding potentials (BP_ND) between TS and HC participants. Analysis of variance was performed to investigate main effect of radioligand. In addition, BP_ND values were extracted for ventral, motor, and associative striatum. Finally, we examined the relationship between BP_ND measures and symptom severity in TS participants. Main effects analyses showed that [¹¹C]‐(+)‐PHNO BP_ND was higher in ventral striatum, whereas [¹¹C]raclopride BP_ND was higher in motor and associative striatum. There were no significant group differences between TS and HC. Furthermore, TS and HC participants had similar [¹¹C]‐(+)‐PHNO and [¹¹C]raclopride BP_ND in the three striatal subregions. Moreover, there was no significant correlation between BP_ND and symptom severity. TS and HC participants had similar striatal D2/3 receptor availability measures. These results challenge the assumption that striatal dopamine receptors have a major role in the pathophysiology of TS. Consistent with previous findings, [¹¹C]‐(+)‐PHNO localized preferentially to ventral striatal, D3 receptor‐rich regions, in contrast to [¹¹C]raclopride, which localized preferentially in the dorsal striatum. Hum Brain Mapp 36:2592–2601, 2015. © 2015 Wiley Periodicals, Inc .     

Imaging in vivo glutamate fluctuations with [11C]ABP688: a GLT-1 challenge with ceftriaxone

Molecular imaging offers unprecedented opportunities for investigating dynamic changes underlying neuropsychiatric conditions. Here, we evaluated whether [¹¹C]ABP688, a positron emission tomography (PET) ligand that binds to the allosteric site of the metabotropic glutamate receptor type 5 (mGluR5), is sensitive to glutamate fluctuations after a pharmacological challenge. For this, we used ceftriaxone (CEF) administration in rats, an activator of the GLT-1 transporter (EAAT2), which is known to decrease extracellular levels of glutamate. MicroPET [¹¹C]ABP688 dynamic acquisitions were conducted in rats after a venous injection of either saline (baseline) or CEF 200 mg/kg (challenge). Binding potentials (BP_ND) were obtained using the simplified reference tissue method. Between-condition statistical parametric maps indicating brain regions showing the highest CEF effects guided placement of microdialysis probes for subsequent assessment of extracellular levels of glutamate. The CEF administration increased [¹¹C]ABP688 BP_ND in the thalamic ventral anterior (VA) nucleus bilaterally. Subsequent microdialysis assessment revealed declines in extracellular glutamate concentrations in the VA. The present results support the concept that availability of mGluR5 allosteric binding sites is sensitive to extracellular concentrations of glutamate. This interesting property of mGluR5 allosteric binding sites has potential applications for assessing the role of glutamate in the pathogenesis of neuropsychiatric conditions.     

Kinetic modeling of the serotonin 5-HT1B receptor radioligand [11C]P943 in humans

[¹¹C]P943 is a new radioligand recently developed to image and quantify serotonin 5-Hydroxytryptamine (5-HT_1B) receptors with positron emission tomography (PET). The purpose of this study was to evaluate [¹¹C]P943 for this application in humans, and to determine the most suitable quantification method. Positron emission tomography data and arterial input function measurements were acquired in a cohort of 32 human subjects. Using arterial input functions, compartmental modeling, the Logan graphical analysis, and the multilinear method MA1 were tested. Both the two tissue-compartment model and MA1 provided good fits of the PET data and reliable distribution volume estimates. Using the cerebellum as a reference region, BP_ND binding potential estimates were computed. [¹¹C]P943 BP_ND estimates were significantly correlated with in vitro measurements of the density of 5-HT_1B receptors, with highest values in the occipital cortex and pallidum. To evaluate noninvasive methods, two- and three-parameter graphical analyses, Simplified Reference Tissue Models (SRTM and SRTM2), and Multilinear Reference Tissue Models (MRTM and MRTM2) were tested. The MRTM2 model provided the best correlation with MA1 binding-potential estimates. Parametric images of the volume of distribution or binding potential of [¹¹C]P943 could be computed using both MA1 and MRTM2. The results show that [¹¹C]P943 provides quantitative measurements of 5-HT_1B binding potential.     

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.     

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.     

Kinetic analysis of the metabotropic glutamate subtype 5 tracer [18F]FPEB in bolus and bolus-plus-constant-infusion studies in humans

[¹⁸F]FPEB is a positron emission tomography tracer which, in preclinical studies, has shown high specificity and selectivity toward the metabotropic glutamate receptor 5 (mGluR5). It possesses the potential to be used in human studies to evaluate mGluR5 function in a range of neuropsychiatric disorders, such as anxiety and Fragile X syndrome. To define optimal scan methodology, healthy human subjects were scanned for 6 hours following either a bolus injection (n=5) or bolus-plus-constant-infusion (n=5) of [¹⁸F]FPEB. Arterial blood samples were collected and parent fraction measured by high-performance liquid chromatography (HPLC) to determine the metabolite-corrected plasma input function. Time activity curves were extracted from 13 regions and fitted by various models to estimate V_T and BP_ND. [¹⁸F]FPEB was well fitted by the two-tissue compartment model, MA1 (t*=30), and MRTM (using cerebellum white matter as a reference). Highest V_T values were observed in the anterior cingulate and caudate, and lowest V_T values were observed in the cerebellum and pallidum. For kinetic modeling studies, V_T and BP_ND were estimated from bolus or bolus-plus-constant-infusion scans as short as 90 minutes. Bolus-plus-constant-infusion of [¹⁸F]FPEB reduced intersubject variability in V_T and allowed equilibrium analysis to be completed with a 30-minute scan, acquired 90–120 minutes after the start of injection.