Faculty Bibliography

Though [(11) C]-(+)-PHNO has enabled quantification of the dopamine-D3 receptor (D3R) in the human brain in vivo, its selectivity for the D3R is not sufficiently high to allow us to disregard its binding to the dopamine-D2 receptor (D2R). We quantified the affinity of [(11) C]-(+)-PHNO for the D2R and D3R in the living primate brain. Two rhesus monkeys were examined on four occasions each, with [(11) C]-(+)-PHNO administered in a bolus + infusion paradigm Varying doses of unlabelled (+)-PHNO were co-administered on each occasion (total doses ranging from 0.09 to 5.61 mug/kg). The regional binding potential (BP(ND) ) and the corresponding doses of injected (+)-PHNO were used as inputs in a model which quantified the affinity of (+)-PHNO for the D2R and D3R, as well as the regional fractions of the [(11) C]-(+)-PHNO signal attributable to D3R binding. (+)-PHNO in vivo affinity for the D3R (K(D) /f(ND) approximately 0.23-0.56 nM) was 25-48 fold higher than that for the D2R (K(D) /f(ND) approximately 11-14 nM). The tracer limits for (+)-PHNO (dose associated with D3R occupancy approximately 10%) were estimated at approximately 0.02-0.04 mug/kg injected mass for anaesthetized primate and at 0.01-0.02 mug/kg for awake human PET studies. Our data enable a rational design and interpretation of future PET studies with [(11) C]-(+)-PHNO. Synapse, 2011. (c) 2011 Wiley-Liss, Inc

[(11)C]MRB is one of the most promising radioligands used to measure brain norepinephrine transporters (NET) with positron emission tomography (PET). The objective of this study was to evaluate the suitability of [(11)C]MRB for drug occupancy studies of NET using atomoxetine (ATX), a NET uptake inhibitor used in the treatment of depression and attention-deficit hyperactivity disorder (ADHD). A second goal of the study was identification of a suitable reference region. Ten PET studies were performed in three anesthetized rhesus monkeys following an infusion of ATX or placebo. [(11)C]MRB arterial input functions and ATX plasma levels were also measured. A dose-dependent reduction of [(11)C]MRB volume of distribution was observed after correction for [(11)C]MRB plasma free fraction. ATX IC(50) was estimated to be 31 +/- 10ng/mL plasma. This corresponds to an effective dose (ED(50)) of 0.13mg/kg, which is much lower than the therapeutic dose of ATX in ADHD (1.0-1.5mg/kg). [(11)C]MRB binding potential BP(ND) in the thalamus was estimated to be 1.8 +/- 0.3. Defining a reference region for a NET radiotracer is challenging due to the widespread and relatively uniform distribution of NET in the brain. Three regions were evaluated for use as reference region: caudate, putamen and occipital cortex. Caudate was found to be the most suitable for preclinical drug occupancy studies in rhesus monkeys. The IC(50) estimate obtained using MRTM2 BP(ND) without arterial blood sampling was 21 +/- 3ng/mL (using caudate as the reference region). This study demonstrated that [(11)C]MRB is suitable for drug occupancy studies of NET

INTRODUCTION: The aim of this study was to evaluate a newly reported positron emission tomography (PET) radioligand [(11)C]MP-10, a potent and selective inhibitor of the central phosphodiesterase 10A enzyme (PDE10A) in vivo, using PET. METHODS: A procedure was developed for labeling MP-10 with carbon-11. [(11)C]MP-10 was evaluated in vivo both in the pig and baboon brain. RESULTS: Alkylation of the corresponding desmethyl compound with [(11)C]methyl iodide produced [(11)C]MP-10 with good radiochemical yield and specific activity. PET studies in the pig showed that [(11)C]MP-10 rapidly entered the brain reaching peak tissue concentration at 1-2 min postadministration, followed by washout from the tissue. Administration of a selective PDE10A inhibitor reduced the binding in all brain regions to the levels of the cerebellum, demonstrating the saturability and selectivity of [(11)C]MP-10 binding. In the nonhuman primate, the brain tissue kinetics of [(11)C]MP-10 were slower, reaching peak tissue concentrations at 30-60 min postadministration. In both species, the observed rank order of regional brain signal was striatum>diencephalon>cortical regions=cerebellum, consistent with the known distribution and concentration of PDE10A. [(11)C]MP-10 brain kinetics were well described by a two-tissue compartment model, and estimates of total volume of distribution (V(T)) were obtained. Blocking studies with unlabeled MP-10 revealed the suitability of the cerebellum as a reference tissue and enabled the estimation of regional binding potential (BP(ND)) as the outcome measure of specific binding. Quantification of [(11)C]MP-10 binding using the simplified reference tissue model with cerebellar input function produced BP(ND) estimates consistent with those obtained by the two-tissue compartment model. CONCLUSION: We demonstrated that [(11)C]MP-10 possesses good characteristics for the in vivo quantification of the PDE10A in the brain by PET

INTRODUCTION: GR103545 is a potent and selective kappa-opioid receptor agonist. Previous studies in non-human primates demonstrated favorable properties of [(11)C]GR103545 as a positron emission tomography tracer for in vivo imaging of cerebral kappa-opioid receptor. Nonetheless, advancement of [(11)C]GR103545 to imaging studies in humans was hampered by difficulties of its multiple-step radiosynthesis, which produces a final product with low specific activity (SA), which in turn could induce undesirable physiological side effects resulting from the mass associated with an injected amount of radioactivity. We report herein an alternative radiosynthesis of [(11)C]GR103545 with higher SA and radiochemical yields. METHODS: The TRACERLab FXC automated synthesis module was used to carry out the two-step, one-pot procedure. In the first step, the desmethoxycarbonyl precursor was converted to the carbamic acid intermediate desmethyl-GR103545 via transcarboxylation with the zwitterionic carbamic complex, 1,8-diazabicyclo[5.4.0]undec-7-ene-carbon dioxide, in the presence and/or absence of cesium carbonate and tetrabutylammonium triflate. In the second step, the intermediate was radiolabeled at the carboxyl oxygen with [(11)C]methyl trifluoromethanesulfonate to give [(11)C]GR103545. RESULTS: This novel synthesis produced [(11)C]GR103545 with >/=90% chemical and radiochemical purities and an SA of 290.45+/-99.9 MBq/nmol at the end of synthesis (n=26). Injectable radioactivity was 1961+/-814 GBq/mumol with 43 min of average synthesis time from the end of beam. CONCLUSION: We have developed a practical one-pot method for the routine production of [(11)C]GR103545 with reliably high SA and radiochemical yield, thus allowing the advancement of this radiotracer to imaging applications in humans

CONTEXT: Serotonergic dysfunction is implicated in the pathogenesis of posttraumatic stress disorder (PTSD), and recent animal models suggest that disturbances in serotonin type 1B receptor function, in particular, may contribute to chronic anxiety. However, the specific role of the serotonin type 1B receptor has not been studied in patients with PTSD. OBJECTIVE: To investigate in vivo serotonin type 1B receptor expression in individuals with PTSD, trauma-exposed control participants without PTSD (TC), and healthy (non-trauma-exposed) control participants (HC) using positron emission tomography and the recently developed serotonin type 1B receptor selective radiotracer [(11)C]P943. DESIGN: Cross-sectional positron emission tomography study under resting conditions. SETTING: Academic and Veterans Affairs medical centers. PARTICIPANTS: Ninety-six individuals in 3 study groups: PTSD (n = 49), TC (n = 20), and HC (n = 27). Main Outcome Measure Regional [(11)C]P943 binding potential (BP(ND)) values in an a priori-defined limbic corticostriatal circuit investigated using multivariate analysis of variance and multiple regression analysis. RESULTS: A history of severe trauma exposure in the PTSD and TC groups was associated with marked reductions in [(11)C]P943 BP(ND) in the caudate, the amygdala, and the anterior cingulate cortex. Participant age at first trauma exposure was strongly associated with low [(11)C]P943 BP(ND). Developmentally earlier trauma exposure also was associated with greater PTSD symptom severity and major depression comorbidity. CONCLUSIONS: These data suggest an enduring effect of trauma history on brain function and the phenotype of PTSD. The association of early age at first trauma and more pronounced neurobiological and behavioral alterations in PTSD suggests a developmental component in the cause of PTSD

PURPOSE: The aim of this study is to compare the utility of two positron emission tomography (PET) imaging ligands ((+)-[(11)C]dihydrotetrabenazine ([(11)C]DTBZ) and the fluoropropyl analog ([(18)F]FP-(+)-DTBZ)) that target islet beta-cell vesicular monoamine transporter type II to measure pancreatic beta-cell mass (BCM). PROCEDURES: [(11)C]DTBZ or [(18)F]FP-(+)-DTBZ was injected, and serial PET images were acquired in rat models of diabetes (streptozotocin-treated and Zucker diabetic fatty) and beta-cell compensation (Zucker fatty). Radiotracer standardized uptake values (SUV) were correlated to pancreas insulin content measured biochemically and histomorphometrically. RESULTS: On a group level, a positive correlation of [(11)C]DTBZ pancreatic SUV with pancreas insulin content and BCM was observed. In the STZ diabetic model, both [(18)F]FP-(+)-DTBZ and [(11)C]DTBZ correlated positively with BCM, although only approximately 25% of uptake could be attributed to beta-cell uptake. [(18)F]FP-(+)-DTBZ displacement studies indicate that there is a substantial fraction of specific binding that is not to pancreatic islet beta cells. CONCLUSIONS: PET imaging with [(18)F]FP-(+)-DTBZ provides a noninvasive means to quantify insulin-positive BCM and may prove valuable as a diagnostic tool in assessing treatments to maintain or restore BCM

[(11)C]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 [(11)C]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. [(11)C]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 [(11)C]P943 could be computed using both MA1 and MRTM2. The results show that [(11)C]P943 provides quantitative measurements of 5-HT(1B) binding potential

Altered cognitive control is implicated in the shaping of cocaine dependence. One of the key component processes of cognitive control is error monitoring. Our previous imaging work highlighted greater activity in distinct cortical and subcortical regions including the dorsal anterior cingulate cortex (dACC), thalamus and insula when participants committed an error during the stop signal task (Li et al., 2008b). Importantly, dACC, thalamic and insular activity has been associated with drug craving. One hypothesis is that the intense interoceptive activity during craving prevents these cerebral structures from adequately registering error and/or monitoring performance. Alternatively, the dACC, thalamus and insula show abnormally heightened responses to performance errors, suggesting that excessive responses to salient stimuli such as drug cues could precipitate craving. The two hypotheses would each predict decreased and increased activity during stop error (SE) as compared to stop success (SS) trials in the SST. Here we showed that cocaine dependent patients (PCD) experienced greater subjective feeling of loss of control and cocaine craving during early (average of day 6) compared to late (average of day 18) abstinence. Furthermore, compared to PCD during late abstinence, PCD scanned during early abstinence showed increased thalamic as well as insular but not dACC responses to errors (SE>SS). These findings support the hypothesis that heightened thalamic reactivity to salient stimuli co-occur with cocaine craving and loss of self control

BACKGROUND: Attention-deficit/hyperactivity disorder is a psychiatric disorder that starts in childhood. The mechanism of action of methylphenidate, the most common treatment for attention deficit hyperactivity disorder, is unclear. In vitro, the affinity of methylphenidate for the norepinephrine transporter (NET) is higher than that for the dopamine transporter (DAT). The goal of this study was to use positron emission tomography to measure the occupancy of brain norepinephrine transporter by methylphenidate in vivo in humans. METHODS: We used (S,S)-[(1)(1)C] methylreboxetine ([(1)(1)C]MRB) to determine the effective dose 50 (ED) of methylphenidate for NET. In a within-subject design, healthy subjects (n = 11) received oral, single-blind placebo and 2.5, 10, and 40 mg of methylphenidate 75 min before [(1)(1)C]MRB injection. Dynamic positron emission tomography imaging was performed for 2 hours with the High Resolution Research Tomograph. The multilinear reference tissue model with occipital cortex as the reference region was used to estimate binding potential non-displaceable (BP(ND)) in the thalamus and other NET-rich regions. RESULTS: BP(ND) was reduced by methylphenidate in a dose-dependent manner in thalamus and other NET-rich regions. The global ED was estimated to be .14 mg/kg; therefore, the average clinical maintenance dose of methylphenidate (.35-.55 mg/kg) produces 70% to 80% occupancy of NET. CONCLUSIONS: For the first time in humans, we demonstrate that oral methylphenidate significantly occupies NET at clinically relevant doses. The ED is lower than that for DAT (.25 mg/kg), suggesting the potential relevance of NET inhibition in the therapeutic effects of methylphenidate in attention-deficit/hyperactivity disorder

OBJECTIVES: The role of the norepinephrine transporter (NET) in cocaine dependence has never been demonstrated via in vivo imaging due to the lack of suitable NET radioligands. Here we report our preliminary studies evaluting the NET in individuals with cocaine dependence (COC) in comparison to healthy controls (HC) using (S,S)-[(11)C]methylreboxetine ([(11)C]MRB), the most promising C-11 labeled positron-emission tomography (PET) radioligand for NET developed to date. METHODS: Twenty two human volunteers (10 COC and 12 HC) underwent dynamic (11)C-MRB-PET acquisition using a High Resolution Research Tomograph (HRRT). Binding potential (BP(ND)) parametric images were computed using the simplified reference tissue model (SRTM2) with occipital cortex as reference region. BP(ND) values were compared between the two groups. RESULTS: Locus coeruleus (LC), hypothalamus, and pulvinar showed a significant inverse correlation with age among HC (age range = 25-54 years; P = 0.04, 0.009, 0.03 respectively). The BP(ND) was significantly increased in thalamus (27%; P < 0.02) and dorsomedial thalamic nuclei (30%; P < 0.03) in COC as compared to HC. Upon age normalization, the upregulation of NET in COC also reached significance in LC (63%, P < 0.01) and pulvinar (55%, P < 0.02) regions. CONCLUSION: Our results suggest that (a) brain NET concentration declines with age in HC, and (b) there is a significant upregulation of NET in thalamus and dorsomedial thalamic nucleus in COC as compared to HC. Our results also suggest that the use of [(11)C]MRB and HRRT provides an effective strategy for studying alterations of the NET system in humans