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PET imaging of synaptic vesicle glycoprotein 2A allows for noninvasive quantification of synapses. This first-in-human study aimed to evaluate the kinetics, test-retest reproducibility, and extent of specific binding of a recently developed synaptic vesicle glycoprotein 2A PET ligand, ( R )-4-(3-( 18 F-fluoro)phenyl)-1-((3-methylpyridin-4-yl)methyl)pyrrolidine-2-one ( 18 F-SynVesT-2), with fast brain kinetics. Methods: Nine healthy volunteers participated in this study and were scanned on a High Resolution Research Tomograph scanner with 18 F-SynVesT-2. Five volunteers were scanned twice on 2 different days. Five volunteers were rescanned with preinjected levetiracetam (20 mg/kg, intravenously). Arterial blood was collected to calculate the plasma free fraction and generate the arterial input function. Individual MR images were coregistered to a brain atlas to define regions of interest for generating time-activity curves, which were fitted with 1- and 2-tissue-compartment (1TC and 2TC) models to derive the regional distribution volume ( V T ). The regional nondisplaceable binding potential ( BP ND ) was calculated from 1TC V T , using the centrum semiovale (CS) as the reference region. Results: 18 F-SynVesT-2 was synthesized with high molar activity (187 ± 69 MBq/nmol, n = 19). The parent fraction of 18 F-SynVesT-2 in plasma was 28% ± 8% at 30 min after injection, and the plasma free fraction was high (0.29 ± 0.04). 18 F-SynVesT-2 entered the brain quickly, with an SUV peak of 8 within 10 min after injection. Regional time-activity curves fitted well with both the 1TC and the 2TC models; however, V T was estimated more reliably using the 1TC model. The 1TC V T ranged from 1.9 ± 0.2 mL/cm 3 in CS to 7.6 ± 0.8 mL/cm 3 in the putamen, with low absolute test-retest variability (6.0% ± 3.6%). Regional BP ND ranged from 1.76 ± 0.21 in the hippocampus to 3.06 ± 0.29 in the putamen. A 20-min scan was sufficient to provide reliable V T and BP ND Conclusion: 18 F-SynVesT-2 has fast kinetics, high specific uptake, and low nonspecific uptake in the brain. Consistent with the nonhuman primate results, the kinetics of 18 F-SynVesT-2 is faster than the kinetics of 11 C-UCB-J and 18 F-SynVesT-1 in the human brain and enables a shorter dynamic scan to derive physiologic information on cerebral blood flow and synapse density., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.) more...

Arginine vasopressin is a hormone that is synthesized mainly in the hypothalamus and stored in the posterior pituitary. Receptors for vasopressin are categorized into at least 3 subtypes (V pt>1A , V 1B , and V 2 ). Among these subtypes, the V 1B receptor (V 1B R), highly expressed in the pituitary, is a primary regulator of hypothalamic-pituitary-adrenal axis activity and thus a potential target for treatment of neuropsychiatric disorders such as depression and anxiety. N - tert -butyl-2-[2-(6-methoxypyridine-2-yl)-6-[3-(morpholin-4-yl)propoxy]-4-oxopyrido[2,3-d]pyrimidin-3(4 H )-yl]acetamide (TASP699) is a novel PET radiotracer with high affinity and selectivity for V 1B R. The purpose of this study was to characterize the pharmacokinetic and binding profiles of 11 C-TASP699 in humans and determine its utility in an occupancy study of a novel V 1B R antagonist, TS-121. Methods: Six healthy subjects were scanned twice with 11 C-TASP699 to determine the most appropriate kinetic model for analysis of imaging data and test-retest reproducibility of outcome measures. Nine healthy subjects were scanned before and after administration of TS-121 (active component: THY1773) to assess V 1B R occupancy. Metabolite-corrected arterial input functions were obtained. Pituitary time-activity curves were analyzed with 1- and 2-tissue-compartment (1TC and 2TC, respectively) models and multilinear analysis 1 (MA1) to calculate distribution volume ( V T ). Relative test-retest variability (TRV) and absolute TRV were calculated. Since no brain region could be used as a reference region, percentage change in V T after TS-121 administration was computed to assess its receptor occupancy and correlate with plasma concentrations of the drug. Results: 11 C-TASP699 showed high uptake in the pituitary and no uptake in any brain region. The 2TC model provided better fits than the 1TC model. Because the MA1 V T estimates were similar to the 2TC V T estimates, MA1 was the model of choice. The TRV of V T was good (TRV, -2% ± 14%; absolute TRV, 11%). THY1773 reduced V T in a dose-dependent fashion, with a half-maximal inhibitory concentration of 177 ± 52 ng/mL in plasma concentration. There were no adverse events resulting in discontinuation from the study. Conclusion: 11 C-TASP699 was shown to display appropriate kinetics in humans, with substantial specific binding and good reproducibility of V T Therefore, this tracer is suitable for measurement of V 1B R in the human pituitary and the V 1B R occupancy of TS-121, a novel V 1B R antagonist., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.) more...

The positron emission tomography radioligand [ 11 C]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 [ 11 C]UCB-J tissue influx ( K 1 ), volume of distribution ( V T ), or binding potential ( BP ND ). Healthy volunteers ( n  = 7) underwent 60-min [ 11 C]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 K 1 were determined using the one-tissue compartment model and BP ND using the simplified reference tissue model. In primary visual cortex, K 1 increased 34.3 ± 15.5% ( p  = 0.001) during stimulation, with no change in other regions ( p s   >   0.12). K 1 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 ( p s   >   0.19). Therefore, despite robust increases in regional tracer influx due to blood flow increases, binding measures were unchanged during stimulation. [ 11 C]UCB-J V T and BP ND are likely to be stable in vivo measures of synaptic density. more...

The use of synaptic vesicle glycoprotein 2A radiotracers with PET imaging could provide a way to measure synaptic density quantitatively in living humans. 11 C-UCB-J (( R )-1-((3-( 11 C-methyl- 11 C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one), previously developed and assessed in nonhuman primates and humans, showed excellent kinetic properties as a PET radioligand. However, it is labeled with the short half-life isotope 11 C. We developed a new tracer, an 18 F-labeled difluoro-analog of UCB-J ( 18 F-SynVesT-1, also known as 18 F-SDM-8), which displayed favorable properties in monkeys. The purpose of this first-in-human study was to assess the kinetic and binding properties of 18 F-SynVesT-1 and compare with 11 C-UCB-J. Methods: Eight healthy volunteers participated in a baseline study of 18 F-SynVesT-1. Four of these subjects were also scanned after a blocking dose of the antiepileptic drug levetiracetam (20 mg/kg). Metabolite-corrected arterial input functions were measured. Regional time-activity curves were analyzed using 1-tissue-compartment (1TC) and 2-tissue-compartment (2TC) models and multilinear analysis 1 to compute total distribution volume ( V T ) and binding potential ( BP ND ). The centrum semiovale was used as a reference region. The Lassen plot was applied to compute levetiracetam occupancy and nondisplaceable distribution volume. SUV ratio-1 (SUVR-1) over several time windows was compared with BP ND Results: Regional time-activity curves were fitted better with the 2TC model than the 1TC model, but 2TC V T estimates were unstable. The 1TC V T values matched well with those from the 2TC model (excluding the unstable values). Thus, 1TC was judged as the most useful model for quantitative analysis of 18 F-SynVesT-1 imaging data. The minimum scan time for stable V T measurement was 60 min. The rank order of V T and BP ND was similar between 18 F-SynVesT-1 and 11 C-UCB-J. Regional V T was slightly higher for 11 C-UCB-J, but BP ND was higher for 18 F-SynVesT-1, though these differences were not significant. Levetiracetam reduced the uptake of 18 F-SynVesT-1 in all regions and produced occupancy of 85.7%. The SUVR-1 of 18 F-SynVesT-1 from 60 to 90 min matched best with 1TC BP ND Conclusion: The novel synaptic vesicle glycoprotein 2A tracer, 18 F-SynVesT-1, displays excellent kinetic and in vivo binding properties in humans and holds great potential for the imaging and quantification of synaptic density in neuropsychiatric disorders., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.) more...

This was a first-in-human study of the PET radiotracer 11 C-LSN3172176 for the muscarinic acetylcholine receptor subtype M1. The objectives of the study were to determine the appropriate kinetic model to quantify binding of the tracer to M1 receptors, and the reliability of the chosen quantification method. Methods: Six healthy subjects completed the test-retest protocol, and 5 healthy subjects completed the baseline-scopolamine blocking protocol. Multiple modeling methods were applied to calculate total distribution volume ( V T ) and nondisplaceable binding potential ( BP ND ) in various brain regions. The reference region was selected from the blocking study. The occupancy plot was applied to compute receptor occupancy by scopolamine and nondisplaceable distribution volume. Results: Tracer uptake was highest in the striatum, followed by neocortical regions and white matter, and lowest in the cerebellum. Regional time-activity curves were fitted well by all models. The 2-tissue-compartment (2TC) model fits were good, but the 2TC parameters often could not be reliably estimated. Because V T correlated well between the 2TC and 1-tissue-compartment (1TC) models after exclusion of unreliable estimates, the 1TC model was chosen as the most appropriate. The cerebellum showed the lowest V T , consistent with preclinical studies showing little to no specific binding in the region. Further, cerebellar V T did not change between baseline and blocking scans, indicating that the cerebellum is a suitable reference region. The simplified reference tissue model (SRTM) slightly underestimated 1TC BP ND , and the simplified reference tissue model 2 (SRTM2) improved BP ND estimation. An 80-min scan was sufficient to quantify V T and BP ND The test-retest study showed excellent absolute test-retest variability for 1TC V T (≤5%) and BP ND (≤10%). In the baseline and blocking studies, occupancy values were lower in the striatum than in nonstriatal regions, as may be attributed to differences in regional acetylcholine concentrations. Conclusion: The 1TC and SRTM2 models are appropriate for quantitative analysis of 11 C-LSN3172176 imaging data. 11 C-LSN3172176 displayed excellent test-retest reproducibility and is a highly promising ligand to quantify M1 receptors in the human brain., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.) more...

11 C-UCB-J (( R )-1-((3-( 11 C-methyl- 11 C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one) is a PET tracer for synaptic vesicle glycoprotein 2A, which may be a marker of synaptic density. To simplify the scan protocol, SUV ratios (SUVRs) were compared with model-based nondisplaceable binding potential ( BP ND ) to select the optimal time window in healthy and neuropsychiatric subjects. Methods: In total, 141 scans were acquired for 90 min. Arterial blood sampling and metabolite analysis were conducted. SUVR-1 (centrum semiovale reference region) was computed for six 30-min windows and compared with 1-tissue-compartment model BP ND Simulations were performed to assess the time dependency of SUVR-1. Results: Greater correlation and less bias were observed for SUVR-1 at later time windows for all subjects. Simulations showed that the agreement between SUVR-1 and BP ND is time-dependent. Conclusion: The 60- to 90-min period provided the best match between SUVR-1 and BP ND (-1% ± 7%); thus, a short scan is sufficient for accurate quantification of 11 C-UCB-J-specific binding., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.) more...

The κ-opioid receptor (KOR) is implicated in various neuropsychiatric disorders. We previously evaluated an agonist tracer, 11 C-GR103545, for PET imaging of KOR in humans. Although 11 C-GR103545 showed high brain uptake, good binding specificity, and selectivity for KOR, it displayed slow kinetics and relatively large test-retest variability of total distribution volume ( V T ) estimates (15%). Therefore, we set out to develop 2 novel KOR agonist radiotracers, 11 C-EKAP and 11 C-FEKAP. In nonhuman primates, both tracers exhibited faster kinetics than 11 C-GR103545 and comparable binding parameters to 11 C-GR103545. The aim of this study was to assess their kinetic and binding properties in humans. Methods: Six healthy subjects underwent 120-min test-retest PET scans with both 11 C-EKAP and 11 C-FEKAP. Metabolite-corrected arterial input functions were measured. Regional time-activity curves were generated for 14 regions of interest. One-tissue-compartment and 2-tissue-compartment (2TC) models and the multilinear analysis-1 (MA1) method were applied to the regional time-activity curves to calculate V T The time stability of V T and test-retest reproducibility were evaluated. Levels of specific binding, as measured by the nondisplaceable binding potential ( BP ND ) for the 3 tracers ( 11 C-EKAP, 11 C-FEKAP, and 11 C-GR103545), were compared using a graphical method. Results: For both tracers, regional time-activity curves were fitted well with the 2TC model and MA1 method ( t * = 20 min) but not with the 1-tissue-compartment model. Given the unreliably estimated parameters in several fits with the 2TC model and a good V T match between MA1 and 2TC, MA1 was chosen as the appropriate model for both tracers. Mean MA1 V T was highest for 11 C-GR103545, followed by 11 C-EKAP and then 11 C-FEKAP. The minimum scan time for stable V T measurement was 90 and 110 min for 11 C-EKAP and 11 C-FEKAP, respectively, compared with 140 min for 11 C-GR103545. The mean absolute test-retest variability in MA1 V T estimates was 7% and 18% for 11 C-EKAP and 11 C-FEKAP, respectively. BP ND levels were similar for 11 C-FEKAP and 11 C-GR103545 but were about 25% lower for 11 C-EKAP. Conclusion: The 2 novel KOR agonist tracers showed faster tissue kinetics than 11 C-GR103545. Even with a slightly lower BP ND , 11 C-EKAP is judged to be a better tracer for imaging and quantification of KOR in humans, on the basis of the shorter minimum scan time and the excellent test-retest reproducibility of regional V T ., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.) more...

Context: Cortisol, a glucocorticoid steroid stress hormone, is primarily responsible for stimulating gluconeogenesis in the liver and promoting adipocyte differentiation and maturation. Prolonged excess cortisol leads to visceral adiposity, insulin resistance, hyperglycemia, memory dysfunction, cognitive impairment, and more severe Alzheimer's disease phenotypes. The intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive cortisone to active cortisol; yet the amount of 11β-HSD1 in the brain has not been quantified directly in vivo., Objective: We analyzed positron emission tomography (PET) scans with an 11β-HSD1 inhibitor radioligand in twenty-eight individuals (23 M/5F): 10 lean, 13 overweight, and 5 obese individuals. Each individual underwent PET imaging on the high-resolution research tomograph PET scanner after injection of 11 C-AS2471907 (n = 17) or 18 F-AS2471907 (n = 11). Injected activity and mass doses were 246 ± 130 MBq and 0.036 ± 0.039 μg, respectively, for 11 C-AS2471907, and 92 ± 15 MBq and 0.001 ± 0.001 μg for 18 F-AS2471907. Correlations of mean whole brain and regional distribution volume (V T ) with body mass index (BMI) and age were performed with a linear regression model., Results: Significant correlations of whole brain mean V T with BMI and age (V T  = 15.23-0.63 × BMI + 0.27 × Age, p = 0.001) were revealed. Age-adjusted mean whole brain V T values were significantly lower in obese individuals. Post hoc region specific analyses revealed significantly reduced mean V T values in the thalamus (lean vs. overweight and lean vs. obese individuals). Caudate, hypothalamus, parietal lobe, and putamen also showed lower V T value in obese vs. lean individuals. A significant age-associated increase of 2.7 mL/cm 3 per decade was seen in BMI-corrected mean whole brain V T values., Conclusions: In vivo PET imaging demonstrated, for the first time, correlation of higher BMI (obesity) with lower levels of the enzyme 11β-HSD1 in the brain and correlation of increased 11β-HSD1 levels in the brain with advancing age. more...

Development of medications selective for dopamine D 2 or D 3 receptors is an active area of research in numerous neuropsychiatric disorders including addiction and Parkinson's disease. The positron emission tomography (PET) radiotracer [ 11 C]-(+)-PHNO, an agonist that binds with high affinity to both D 2 and D 3 receptors, has been used to estimate relative receptor subtype occupancy by drugs based on a priori knowledge of regional variation in the expression of D 2 and D 3 receptors. The objective of this work was to use a data-driven independent component analysis (ICA) of receptor blocking scans to separate D 2 -and D 3 -related signal in [ 11 C]-(+)-PHNO binding data in order to improve the precision of subtype specific measurements of binding and occupancy. Eight healthy volunteers underwent [ 11 C]-(+)-PHNO PET scans at baseline and at two time points following administration of the D 3 -preferring antagonist ABT-728 (150-1000 ​mg). Parametric binding potential (BP ND ) images were analyzed as four-dimensional image series using ICA to extract two independent sources of variation in [ 11 C]-(+)-PHNO BP ND . Spatial source maps for each component were consistent with respective regional patterns of D 2 -and D 3 -related binding. ICA-derived occupancy estimates from each component were similar to D 2 -and D 3 -specific occupancy estimated from a region-based approach (intraclass correlation coefficients ​> ​0.95). ICA-derived estimates of D 3 receptor occupancy improved quality of fit to a single site binding model. Furthermore, ICA-derived estimates of the regional fraction of [ 11 C]-(+)-PHNO binding related to D 3 receptors was generated for each subject and values showed good agreement with region-based model estimates and prior literature values. In summary, ICA successfully separated D 2 -and D 3 -related components of the [ 11 C]-(+)-PHNO binding signal, establishing this approach as a powerful data-driven method to quantify distinct biological features from PET data composed of mixed data sources., Competing Interests: Declaration of competing interest None., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.) more...

Background: Previous imaging studies using Positron Emission Tomography (PET) have shown that alcohol use disorder (AUD) is associated with a decrease in dopamine type 2/3 receptor (D 2/3 ) binding and dopamine transmission. Although binge drinking is a risk factor for future AUD, little is known about the neurobiology of binge drinking in young adults. This study measured D 2/3 receptor binding and stimulant-induced dopamine release using PET and [ 11 C]raclopride in binge drinkers without an AUD., Methods: This study included 14 healthy controls (HC) and 14 young adult binge drinkers (BD), aged 18-25. The BD met National Institute on Alcohol Abuse and Alcoholism (NIAAA) criteria for binge drinking and the HC subjects were social drinkers. The subjects were scanned with [ 11 C]raclopride before and after the administration of oral methylphenidate (60 mg) to measure D 2/3 binding and dopamine release., Results: There was no significant difference in the PET measures of D 2/3 binding or methylphenidate-induced dopamine release between the two groups. There was no significant association between Alcohol Use Disorders Identification Test (AUDIT) scores or 30-day drinking history and the imaging data., Conclusion: In this sample of 18-25-year-old binge drinkers without a diagnosis of a substance use disorder, there were no significant differences in D 2/3 receptor binding potential or methylphenidate-induced dopamine release relative to healthy controls., (Copyright © 2019 Elsevier B.V. All rights reserved.) more...

The 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme converts cortisone to cortisol and participates in the regulation of glucocorticoid levels in tissues. 11β-HSD1 is expressed in the liver, kidney, adipose tissue, placenta, and brain. 11β-HSD1 is a target for treatment of depression, anxiety, posttraumatic stress disorder, and also against age-related cognitive function and memory loss. In this study, we evaluated the radiotracer 11 C-AS2471907 (3-(2-chlorophenyl)-4-(methyl- 11 C )-5-[2-[2,4,6-trifluorophenoxy]propan-2-yl]-4 H -1,2,4-triazole) to image 11β-HSD1 availability in the human brain with PET. Methods: Fifteen subjects were included in the study. All subjects underwent one 2-h scan after a bolus administration of 11 C-AS2471907. Two subjects underwent an additional scan after blockade with the selective and high-affinity 11β-HSD1 inhibitor ASP3662 to evaluate 11 C-AS2471907 nondisplaceable distribution volume. Five subjects also underwent an additional scan to evaluate the within-day test-retest variability of 11 C-AS2471907 volumes of distribution ( V T ). Results: 11 C-AS2471907 time-activity curves were best fitted by the 2-tissue-compartment (2TC) model. 11 C-AS2471907 exhibited a regionally varying pattern of uptake throughout the brain. The V T of 11 C-AS2471907 ranged from 3.7 ± 1.5 mL/cm 3 in the caudate nucleus to 14.5 ± 5.3 mL/cm 3 in the occipital cortex, with intermediate values in the amygdala, white matter, cingulum, insula, frontal cortex, putamen, temporal and parietal cortices, cerebellum, and thalamus (from lowest to highest V T ). From the blocking scans, nondisplaceable distribution volume was determined to be 0.16 ± 0.04 mL/cm 3 for 11 C-AS2471907. Thus, nearly all uptake was specific and the binding potential ranged from 22 in the caudate to 90 in the occipital cortex. Test-retest variability of 2TC V T values was less than 10% in most large cortical regions (14% in parietal cortex) and ranged from 14% (cerebellum) to 51% (amygdala) in other regions. The intraclass correlation coefficient of 2TC V T values ranged from 0.55 in the white matter to 0.98 in the cerebellum. Conclusion: 11 C-AS2471907 has a high fraction of specific binding in vivo in humans and reasonable within-day reproducibility of binding parameters., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.) more...

The M 1 muscarinic acetylcholine receptor (mAChR) plays an important role in learning and memory, and therefore is a target for development of drugs for treatment of cognitive impairments in Alzheimer disease and schizophrenia. The availability of M 1 -selective radiotracers for PET will help in developing therapeutic agents by providing an imaging tool for assessment of drug dose-receptor occupancy relationship. Here we report the synthesis and evaluation of 11 C-LSN3172176 (ethyl 4-(6-(methyl- 11 C )-2-oxoindolin-1-yl)-[1,4'-bipiperidine]-1'-carboxylate) in nonhuman primates. Methods: 11 C-LSN3172176 was radiolabeled via the Suzuki-Miyaura cross-coupling method. PET scans in rhesus macaques were acquired for 2 h with arterial blood sampling and metabolite analysis to measure the input function. Blocking scans with scopolamine (50 μg/kg) and the M 1 -selective agent AZD6088 (0.67 and 2 mg/kg) were obtained to assess tracer binding specificity and selectivity. Regional brain time-activity curves were analyzed with the 1-tissue-compartment model and the multilinear analysis method (MA1) to calculate regional distribution volume. Nondisplaceable binding potential values were calculated using the cerebellum as a reference region. Results: 11 C-LSN3172176 was synthesized with greater than 99% radiochemical purity and high molar activity. In rhesus monkeys, 11 C-LSN3172176 metabolized rapidly (29% ± 6% parent remaining at 15 min) and displayed fast kinetics and extremely high uptake in the brain. Imaging data were modeled well with the 1-tissue-compartment model and MA1 methods. MA1-derived distribution volume values were high (range, 10-81 mL/cm 3 ) in all known M 1 mAChR-rich brain regions. Pretreatment with scopolamine and AZD6088 significantly reduced the brain uptake of 11 C-LSN3172176, thus demonstrating its binding specificity and selectivity in vivo. The cerebellum appeared to be a suitable reference region for derivation of nondisplaceable binding potential, which ranged from 2.42 in the globus pallidus to 8.48 in the nucleus accumbens. Conclusion: 11 C-LSN3172176 exhibits excellent in vivo binding and imaging characteristics in nonhuman primates and appears to be the first appropriate radiotracer for PET imaging of human M 1 AChR., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.) more...

Studies have shown κ-opioid receptor (KOR) abnormalities in addictive disorders, other central nervous system diseases, and Alzheimer's disease. We have developed the first set of agonist pt>11 C-GR103545 and antagonist 11 C-LY2795050 radiotracers for PET imaging of KOR in humans. Nonetheless, 11 C-GR103545 displays protracted uptake kinetics and is not an optimal radiotracer. Here, we report the development and evaluation of 11 C - methyl-( R )-4-(2-(3,4-dichlorophenyl)acetyl)-3-((diethylamino)methyl)piperazine-1-carboxylate ( 11 C-EKAP) and its comparison with 11 C-GR103545. Methods: EKAP was synthesized and assayed for in vitro binding affinities and then radiolabeled. PET studies were performed on rhesus monkeys. Blocking studies were performed with naloxone and the selective KOR antagonists LY2795050 and LY2456302. Arterial input functions were generated for use in kinetic modeling. Brain TACs were analyzed with multilinear analysis 1 to derive binding parameters. Results: EKAP has high KOR affinity (inhibition constant, 0.28 nM) and good selectivity in vitro. 11 C-EKAP was prepared in good radiochemical purity. 11 C-EKAP rapidly metabolized in plasma and displayed fast and reversible kinetics in brain, with peak uptake at less than 20 min after injection. Preblocking with naloxone (1 mg/kg) or LY2795050 (0.2 mg/kg) produced 84%-89% receptor occupancy, whereas LY2456302 (0.05 and 0.3 mg/kg) dose-dependently reduced 11 C-EKAP-specific binding, thus demonstrating its binding specificity and selectivity in vivo. Mean multilinear analysis 1-derived nondisplaceable binding potential values were 1.74, 1.79, 1.46, 0.80, and 0.77 for cingulate cortex, globus pallidus, insula, striatum, and frontal cortex, respectively, consistent with the known KOR distribution in primate brains. Conclusion: We have successfully developed 11 C-EKAP as a KOR agonist tracer with dual attractive imaging properties of fast uptake kinetics and high specific binding in vivo., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.) more...

A series consisting of substituted benzoylbenzamide derivatives of 17α-E-vinyl estradiol 6a-i and 7a-d was prepared in good overall yields from the corresponding novel iodinated benzoylbenzamide precursors using Pd(0)-catalyzed Stille coupling. Biological evaluation using competitive binding assays indicated that all compounds were effective ligands for the ERα- and ERβ-LBD (RBA = 0.5-10.0% of estradiol). Most of the compounds expressed lower stimulatory (agonist) potency (RSA <0.2-0.5%) compared to their binding affinity, however, the meta-substituted isomer 6h demonstrated a level of efficacy (RSA = 5.7%) comparable to its affinity (RBA = 9.5%). Docking studies of 6b, 6h, and 6i with the 2YAT crystal structure suggested that higher affinity and efficacy of 6h are due to an effective set of interactions with exposed receptor sidechains not observed with the ortho- and para- isomers. In this binding model, the terminal ring of the ligand is exposed to the solvent space, which would explain both the small variation in RBA values and the narrow SAR for the diverse structural features., (Copyright © 2019 Elsevier Inc. All rights reserved.) more...

Structural disruption and alterations of synapses are associated with many brain disorders including Alzheimer's disease, epilepsy, depression, and schizophrenia. We have previously developed the PET radiotracer 11 C-UCB-J for imaging and quantification of synaptic vesicle glycoprotein 2A (SV2A) and synaptic density in nonhuman primates and humans. Here we report the synthesis of a novel radiotracer 18 F-SDM-8 and its in vivo evaluation in rhesus monkeys. The in vitro binding assay of SDM-8 showed high SV2A binding affinity ( K i = 0.58 nM). 18 F-SDM-8 was prepared in high molar activity (241.7 MBq/nmol) and radiochemical purity (>98%). In the brain, 18 F-SDM-8 displayed very high uptake with peak standardized uptake value (SVU) greater than 8 and fast and reversible kinetics. A displacement study with levetiracetam and blocking studies with UCB-J and levetiracetam demonstrated its binding reversibility and specificity toward SV2A. Regional binding potential values were calculated and ranged from 0.8 in the brainstem to 4.5 in the cingulate cortex. By comparing to 11 C-UCB-J, 18 F-SDM-8 displayed the same attractive imaging properties: very high brain uptake, appropriate tissue kinetics, and high levels of specific binding. Given the longer half-life of F-18 and the feasibility for central production and multisite distribution, 18 F-SDM-8 holds promise as an excellent radiotracer for SV2A and as a biomarker for synaptic density measurement in neurodegenerative diseases and psychiatric disorders. more...

Purpose: Previous studies demonstrated the utility of [ 18 F]fluoropropyl-(+)-dihydrotetrabenazine ([ 18 F]FP-(+)-DTBZ) as a positron emission tomography (PET) radiotracer for the vesicular monoamine transporter type 2 (VMAT2) to quantify beta cell mass in healthy control (HC) and type 1 diabetes mellitus (T1DM) groups. Quantification of specific binding requires measurement of non-displaceable uptake. Our goal was to identify a reference tissue (renal cortex or spleen) to quantify pancreatic non-specific binding of [ 18 F]FP-(+)-DTBZ with the inactive enantiomer, [ 18 F]FP-(-)-DTBZ. This was the first human study of [ 18 F]FP-(-)-DTBZ., Procedures: Six HCs and four T1DM patients were scanned on separate days after injection of [ 18 F]FP-(+)-DTBZ or [ 18 F]FP-(-)-DTBZ. Distribution volumes (V T ) and standardized uptake values (SUVs) were compared between groups. Three methods for calculation of non-displaceable uptake (V ND ) or reference SUV were applied: (1) use of [ 18 F]FP-(+)-DTBZ reference V T as V ND , assuming V ND is uniform across organs; (2) use of [ 18 F]FP-(-)-DTBZ pancreatic V T as V ND , assuming that V ND is uniform between enantiomers in the pancreas; and (3) use of a scaled [ 18 F]FP-(+)-DTBZ reference V T as V ND , assuming that a ratio of non-displaceable uptake between organs is uniform between enantiomers. Group differences in V T (or SUV), binding potential (BP ND ), or SUV ratio (SUVR) were estimated using these three methods., Results: [ 18 F]FP-(-)-DTBZ V T values were different among organs, and V T (+) and V T (-) were also different in the renal cortex and spleen. Method 3 with the spleen to estimate V ND (or reference SUV) gave the highest non-displaceable uptake and the largest HC vs. T1DM group differences. Significant group differences were also observed in V T (or SUV) with method 1 using spleen. SUV was affected by differences in the input function between groups and between enantiomers., Conclusions: Non-displaceable uptake was different among organs and between enantiomers. Use of scaled spleen V T values for V ND is a suitable method for quantification of VMAT2 in the pancreas. more...

Background: Electronic cigarettes (ECs) can influence nicotine addiction by delivering aerosolized nicotine. We investigated if nicotine from ECs is delivered to the brain β2*-nicotinic acetylcholine receptors (β2*-nAChR) and how this relates to the behavioral effects and nicotine delivery from cigarettes., Methods: Seven nicotine users participated in positron emission tomography (PET) studies with (-)-[18F]Flubatine before and after nicotine challenge with 0, 8, and 36 mg/ml nicotine in a 3.3 Volt, 1.5 Ohm EC or a standard tobacco cigarette. Craving was evaluated before and after product use., Results: Average β2*-nAChR occupancy was higher after 36 mg/ml EC challenge compared to 8 mg/ml EC at trend level. Average β2*-nAChR occupancy after tobacco cigarette smoking was 68 ± 18% and was not different compared with 8 mg/ml (64 ± 17%,) or 36 mg/ml (84 ± 3%) nicotine in EC users. Area under the curve (AUC) of blood nicotine level was higher in the cigarette smoking group compared with the 8mg/ml group (p = 0.03), but similar compared with the 36 mg/ml EC (p = 0.29). Drug craving was reduced after use of the tobacco cigarette, 8 mg/ml EC, and 36 mg/ml EC., Conclusions: In this novel investigation of EC effects at β2*-nAChRs, we show that average β2*-nAChR occupancy was higher after 36 mg/ml EC challenge compared with 8 mg/ml EC. Receptor occupancy and arterial blood nicotine levels after cigarette smoking were similar to 36 mg/ml EC use under controlled conditions. These findings suggest that the ECs studied here have abuse liability and may provide an adequate alternative nicotine delivery system for cigarette smokers., Implications: This is the first study to directly determine the neurologic effects of electronic cigarettes on human brain beta-2 nicotinic acetylcholine receptors using PET neuroimaging with (-)-[18F]Flubatine, a novel radiotracer. Our findings suggest that the e-cigarettes studied here have abuse liability and may provide an adequate alternative nicotine delivery system for cigarette smokers. more...

The lysophosphatidic acid receptor type 1 (LPA1) is 1 of 6 known receptors of the extracellular signaling molecule lysophosphatidic acid. It mediates effects such as cell proliferation, migration, and differentiation. In the lung, LPA1 is involved in pathways leading, after lung tissue injury, to pulmonary fibrosis instead of normal healing, by mediating fibroblast recruitment and vascular leakage. Thus, a LPA1 PET radiotracer may be useful for studying lung fibrosis or for developing LPA1-targeting drugs. We developed and evaluated the radiotracer 11 C-BMT-136088 (1-(4'-(3-methyl-4-(((1( R )-(3- 11 C-methylphenyl)ethoxy)carbonyl)amino)isoxazol-5-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid) in rhesus monkeys to image LPA1 in the lung in vivo with PET. Methods: The study consisted of 3 parts: test-retest scans; self-saturation to estimate the tracer's in vivo dissociation constant, nondisplaceable volume of distribution ( V ND ), and nondisplaceable binding potential ( BP ND ); and dosimetry. In the first 2 parts, the radiotracer was administered using a bolus-plus-infusion protocol, the arterial input function was measured, and the animals underwent 2 scans per day separated by about 4 h. Lung regions of interest were segmented, and the tissue density estimated, from CT images. A fixed blood volume correction was applied. The tracer volume of distribution ( V T ) was estimated using multilinear analysis 1 (MA1) or equilibrium analysis (EA). Results: 11 C-BMT-136088 baseline V T was 1.83 ± 0.16 (MA1, n = 5) or 2.1 ± 0.55 (EA, n = 7) mL of plasma per gram of tissue in the left and right lung regions of interest, with a test-retest variability of -6% (MA1, n = 1) or -1% ± 14% (EA, n = 2). For the self-saturation study, 11 C-BMT-136088 V ND and BP ND were estimated to be 0.9 ± 0.08 mL of plasma per gram of tissue and 1.1 ± 0.14, respectively. The unlabeled drug dose and plasma concentration leading to a 50% reduction of 11 C-BMT-136088 specific binding were 73 ± 30 nmol/kg and 28 ± 12 nM, respectively. The average plasma free fraction was 0.2%; thus, the tracer's in vivo dissociation constant was estimated to be 55 pM. For the dosimetry study, the highest organ dose was in the liver (43.1 ± 4.9 and 68.9 ± 9.4 μSv/MBq in reference human male and female phantoms, respectively), and the effective dose equivalent was 6.9 ± 0.6 and 8.7 ± 0.6 μSv/MBq, respectively. Conclusion: Specific binding of 11 C-BMT-136088 can be reliably measured to quantify LPA1 in the lungs of rhesus monkeys in vivo., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.) more...

The κ-opioid receptor (KOR) has been implicated in depression, addictions, and other central nervous system disorders and, thus, is an important target for drug development. We previously developed several 11 C-labeled PET radiotracers for KOR imaging in humans. Here we report the synthesis and evaluation of 18 F-LY2459989 as the first 18 F-labeled KOR antagonist radiotracer in nonhuman primates and its comparison with 11 C-LY2459989. Methods: The novel radioligand 18 F-LY2459989 was synthesized by 18 F displacement of a nitro group or an iodonium ylide. PET scans in rhesus monkeys were obtained on a small-animal scanner to assess the pharmacokinetic and in vivo binding properties of the ligand. Metabolite-corrected arterial activity curves were measured and used as input functions in the analysis of brain time-activity curves and the calculation of binding parameters. Results: With the iodonium ylide precursor, 18 F-LY2459989 was prepared at high radiochemical yield (36% ± 7% [mean ± SD]), radiochemical purity (>99%), and mean molar activity (1,175 GBq/μmol; n = 6). In monkeys, 18 F-LY2459989 was metabolized at a moderate rate, with a parent fraction of approximately 35% at 30 min after injection. Fast and reversible kinetics were observed, with a regional peak uptake time of less than 20 min. Pretreatment with the selective KOR antagonist LY2456302 (0.1 mg/kg) decreased the activity level in regions with high levels of binding to that in the cerebellum, thus demonstrating the binding specificity and selectivity of 18 F-LY2459989 in vivo. Regional time-activity curves were well fitted by the multilinear analysis 1 kinetic model to derive reliable estimates of regional distribution volumes. With the cerebellum as the reference region, regional binding potentials were calculated and ranked as follows: cingulate cortex > insula > caudate/putamen > frontal cortex > temporal cortex > thalamus, consistent with the reported KOR distribution in the monkey brain. Conclusion: The evaluation of 18 F-LY2459989 in nonhuman primates demonstrated many attractive imaging properties: fast tissue kinetics, specific and selective binding to the KOR, and high specific binding signals. A side-by-side comparison of 18 F-LY2459989 and 11 C-LY2459989 indicated similar kinetic and binding profiles for the 2 radiotracers. Taken together, the results indicated that 18 F-LY2459989 appears to be an excellent PET radiotracer for the imaging and quantification of the KOR in vivo., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.) more...

Purpose: The α 7 nicotinic acetylcholine receptor (nAChR) is implicated in many neuropsychiatric disorders, making it an important target for positron emission tomography (PET) imaging. The first aim of this work was to compare two α 7 nAChRs PET radioligands, [ 18 F]ASEM (3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-([ 18 F]fluorodibenzo[b,d]thiophene 5,5-dioxide) and [ 18 F]DBT-10 (7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-([ 18 F]fluorodibenzo[b,d]thiophene 5,5-dioxide), in nonhuman primates. The second aim was to assess further the quantification and test-retest variability of [ 18 F]ASEM in humans., Methods: PET scans with high specific activity [ 18 F]ASEM or [ 18 F]DBT-10 were acquired in three rhesus monkeys (one male, two female), and the kinetic properties of these radiotracers were compared. Additional [ 18 F]ASEM PET scans with blocking doses of nicotine, varenicline, and cold ASEM were acquired separately in two animals. Next, six human subjects (five male, one female) were imaged with [ 18 F]ASEM PET for 180 min, and arterial sampling was used to measure the parent input function. Different modeling approaches were compared to identify the optimal analysis method and scan duration for quantification of [ 18 F]ASEM distribution volume (V T ). In addition, retest scans were acquired in four subjects (three male, one female), and the test-retest variability of V T was assessed., Results: In the rhesus monkey brain [ 18 F]ASEM and [ 18 F]DBT-10 exhibited highly similar kinetic profiles. Dose-dependent blockade of [ 18 F]ASEM binding was observed, while administration of either nicotine or varenicline did not change [ 18 F]ASEM V T . [ 18 F]ASEM was selected for further validation because it has been used in humans. Accurate quantification of [ 18 F]ASEM V T in humans was achieved using multilinear analysis with at least 90 min of data acquisition, resulting in V T values ranging from 19.6 ± 2.5 mL/cm 3 in cerebellum to 25.9 ± 2.9 mL/cm 3 in thalamus. Test-retest variability of V T was 11.7 ± 9.8%., Conclusions: These results confirm [ 18 F]ASEM as a suitable radiotracer for the imaging and quantification of α 7 nAChRs in humans. more...

Measurements of drug occupancies using positron emission tomography (PET) can be biased if the radioligand concentration exceeds "tracer" levels. Negative bias would also arise in successive PET scans if clearance of the radioligand is slow, resulting in a carryover effect. We developed a method to (1) estimate the in vivo dissociation constant K d of a radioligand from PET studies displaying a non-tracer carryover (NTCO) effect and (2) correct the NTCO bias in occupancy studies taking into account the plasma concentration of the radioligand and its in vivo K d . This method was applied in a study of healthy human subjects with the histamine H 3 receptor radioligand [ 11 C]GSK189254 to measure the PK-occupancy relationship of the H 3 antagonist PF-03654746. From three test/retest studies, [ 11 C]GSK189254 K d was estimated to be 9.5 ± 5.9 pM. Oral administration of 0.1 to 4 mg of PF-03654746 resulted in occupancy estimates of 71%-97% and 30%-93% at 3 and 24 h post-drug, respectively. NTCO correction adjusted the occupancy estimates by 0%-15%. Analysis of the relationship between corrected occupancies and PF-03654746 plasma levels indicated that PF-03654746 can fully occupy H 3 binding sites ( RO max  = 100%), and its IC 50 was estimated to be 0.144 ± 0.010 ng/mL. The uncorrected IC 50 was 26% higher. more...

1. Unbound brain drug concentration (C b,u ), a valid surrogate of interstitial fluid drug concentration (C ISF ), cannot be directly determined in humans, which limits accurately defining the human C b,u :C p,u of investigational molecules. 2. For the H 3 R antagonist (1R,3R)-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-lmethyl)phenyl]cyclobutane-1-carboxamide (PF-03654746), we interrogated C b,u :C p,u in humans and nonhuman primate (NHP). 3. In rat, PF-03654746 achieved net blood-brain barrier (BBB) equilibrium (C b,u :C p,u of 2.11). 4. In NHP and humans, the PET receptor occupancy-based C p,u IC 50 of PF-03654746 was 0.99 nM and 0.31 nM, respectively, which were 2.1- and 7.4-fold lower than its in vitro human H 3 K i (2.3 nM). 5. In an attempt to understand this higher-than-expected potency in humans and NHP, rat-derived C b,u :C p,u of PF-03654746 was integrated with C p,u IC 50 to identify unbound (neuro) potency of PF-03654746, nIC 50 . 6. The nIC 50 of PF-03654746 was 2.1 nM in NHP and 0.66 nM in human which better correlated (1.1- and 3.49-fold lower) with in vitro human H 3 K i (2.3 nM). 7. This correlation of the nIC 50 and in vitro hH 3 K i suggested the translation of net BBB equilibrium of PF-03654746 from rat to NHP and humans, and confirmed the use of C p,u as a reliable surrogate of C b,u . 8. Thus, nIC 50 quantitatively informed the human C b,u :C p,u of PF-03654746. more...

Introduction: 18 F-Fluoropropyl-(+)-dihydrotetrabenazine ( 18 F-FP-(+)-DTBZ) is a vesicular monoamine transporter type 2 (VMAT2) radiotracer for positron emission tomography (PET) imaging to quantify human β-cell mass. Renal cortex and spleen have been suggested as reference regions, however, little is known about 18 F-FP-(+)-DTBZ binding in these regions including the fraction of radiometabolite. We compared the kinetics of 18 F-FP-(+)-DTBZ and its inactive enantiomer 18 F-FP-(-)-DTBZ in baboons, estimated the non-displaceable binding (V ND ) of the tracers, and used ex vivo studies to measure radiometabolite fractions., Methods: PET scans were conducted for up to 4h with (+) and (-) enantiomers. Displacement experiments using unlabeled (+) and (-) enantiomers of FP-DTBZ and fluvoxamine (to evaluate sigma-1 receptor binding) were performed. SUV curves were used to calculate displacement values in the pancreas, renal cortex, and spleen. Distribution volumes (V T ) were computed, and three approaches for calculation of V ND were compared: (1) 18 F-FP-(+)-DTBZ reference V T , (2) 18 F-FP-(-)-DTBZ pancreatic V T , and (3) a scaled 18 F-FP-(+)-DTBZ reference V T values. Ex vivo study was conducted to measure radiometabolite fraction in homogenized tissue samples from baboons at 90min post-injection., Results: Spleen uptake was lowest for both tracers. Highest uptake was in the pancreas with 18 F-FP-(+)-DTBZ and renal cortex with 18 F-FP-(-)-DTBZ. Substantial displacement effect was observed only with unlabeled FP-(+)-DTBZ in the 18 F-FP-(+)-DTBZ studies. Radiometabolite fraction was higher in the renal cortex than the spleen. Approaches (1) and (3) with spleen to estimate V ND provided lowest inter-subject variability of BP ND ., Conclusions: V T differences among organs and between enantiomers indicated that scaling of reference region values is needed for quantification of VMAT2 binding in the pancreas with 18 F-FP-(+)-DTBZ. Since the kidney PET signal has greater partial volume averaging and more radiometabolites, the spleen was considered a more practical candidate for use as a scaled-reference region in the quantification of 18 F-FP-(+)-DTBZ in the pancreas., (Copyright © 2016 Elsevier Inc. All rights reserved.) more...

Unlabelled: This was a first-in-human study of the novel phosphodiesterase-2A (PDE2A) PET ligand (18)F-PF-05270430. The primary goals were to determine the appropriate tracer kinetic model to quantify brain uptake and to examine the within-subject test-retest variability., Methods: In advance of human studies, radiation dosimetry was determined in nonhuman primates. Six healthy male subjects participated in a test-retest protocol with dynamic scans and metabolite-corrected input functions. Nine brain regions of interest were studied, including the striatum, white matter, neocortical regions, and cerebellum. Multiple modeling methods were applied to calculate volume of distribution (VT) and binding potentials relative to the nondisplaceable tracer in tissue (BPND), concentration of tracer in plasma (BPP), and free tracer in tissue (BPF). The cerebellum was selected as a reference region to calculate binding potentials., Results: The dosimetry study provided an effective dose of less than 0.30 mSv/MBq, with the gallbladder as the critical organ; the human target dose was 185 MBq. There were no adverse events or clinically detectable pharmacologic effects reported. Tracer uptake was highest in the striatum, followed by neocortical regions and white matter, and lowest in the cerebellum. Regional time-activity curves were well fit by multilinear analysis-1, and a 70-min scan duration was sufficient to quantify VT and the binding potentials. BPND, with mean values ranging from 0.3 to 0.8, showed the best intrasubject and intersubject variability and reliability. Test-retest variability in the whole brain (excluding the cerebellum) of VT, BPND, and BPP were 8%, 16%, and 17%, respectively., Conclusion: (18)F-PF-05270430 shows promise as a PDE2A PET ligand, albeit with low binding potential values., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.) more...