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Arginine vasopressin (AVP) is a hormone that is mainly synthesized in the hypothalamus and stored in the posterior pituitary. Receptors for vasopressin are categorized into at least three subtypes (V1A, V1B, V2). Among these subtypes, the V1B receptor (V1BR), highly expressed in the pituitary, is a primary regulator of the hypothalamic-pituitary-adrenal axis activity, and thus a potential target for the treatment of neuropsychiatric disorders, such as depression and anxiety. 11C-TASP699 is a novel PET radiotracer with high affinity and selectivity for the V1BR. The purpose of this study was to characterize the pharmacokinetic and binding profiles of 11C-TASP699 in human and determine its utility in an occupancy study of a novel V1BR antagonist, TS-121. Methods: Six healthy subjects were scanned twice with 11C-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 V1BR occupancy. Metabolite-corrected arterial input functions were obtained. Pituitary time-activity curves were analyzed with one- and two-tissue compartment (1TC, 2TC) models and multilinear analysis 1 (MA1) to calculate distribution volumes (V T). Relative test-retest variability (TRV) and absolute test-retest variability (aTRV) were calculated. Since no brain region could be used as a reference region, percent change in V T after TS-121 administration was computed to assess its receptor occupancy and correlate with plasma concentration of the drug. Results: 11C-TASP699 showed high uptake in the pituitary and no uptake in any brain regions. The 2TC model provided better fits than the 1TC model. The MA1 V T estimates were very similar to the 2TC V T estimates, so MA1 was the model of choice. TRV of V T was good (TRV: -2 ± 14%, aTRV: 11%). THY1773 reduced VT in a dose-dependent fashion, with IC50 of 177 ± 52 ng/mL in plasma concentration. There were no adverse events resulting in discontinuation from the study. Conclusion: 11C-TASP699 was shown to display appropriate kinetics in human with substantial specific binding and good reproducibility of V T Therefore, this tracer is suitable for measurement of the V1BR in human pituitary and V1BR occupancy of TS-121, a novel V1BR antagonist.

The use of synaptic vesicle protein 2A (SV2A) radiotracers with positron emission tomography (PET) imaging could provide a way to measure synaptic density quantitatively in living humans. 11C-UCB-J, 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 11C. We developed a new tracer, an 18F-labeled difluoro-analog of UCB-J (18F-SynVesT-1, a.k.a. 18F-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 18F-SynVesT-1 and compare with 11C-UCB-J. Methods: Eight healthy volunteers participated in a baseline study of 18F-SynVesT-1. Four of these subjects were also scanned after a blocking dose of the anti-epileptic drug levetiracetam (20 mg/kg). Metabolite-corrected arterial input functions were measured. Regional time-activity curves (TACs) were analyzed using one- and two-tissue compartment (1TC, 2TC) models and multilinear analysis 1 (MA1) to compute distribution volume (VT) and binding potential (BPND). The centrum semiovale was used as a reference region. The Lassen plot was applied to compute levetiracetam occupancy and non-displaceable distribution volume (VND). Standardized uptake value ratio (SUVR) -1 over several time windows was compared with BPND. Results: Regional TACs were fitted better with the 2TC model than the 1TC model, but 2TC VT estimates were unstable. The 1TC VT 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 18F-SynVesT-1 imaging data. Minimum scan time for stable VT measurement was 60 min. The rank order of VT and BPND values was similar between 18F-SynVesT-1 and 11C-UCB-J. Regional VT values were slightly higher for 11C-UCB-J, but BPND values were higher for 18F-SynVesT-1, though these differences were not significant. Levetiracetam reduced the uptake of 18F-SynVesT-1 in all regions and produced occupancy of 85.7%. SUVR-1 of 18F-SynVesT-1 from 60-90 min matched best with 1TC BPND. Conclusion: The novel SV2A tracer, 18F-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.

This was a first-in-human study of the PET radiotracer 11C-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 (VT) and nondisplaceable binding potential (BPND) 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 VT 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 VT, consistent with preclinical studies showing little to no specific binding in the region. Further, cerebellar VT 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 BPND, and the simplified reference tissue model 2 (SRTM2) improved BPND estimation. An 80-min scan was sufficient to quantify VT and BPND. The test–retest study showed excellent absolute test–retest variability for 1TC VT (≤5%) and BPND (≤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 11C-LSN3172176 imaging data. 11C-LSN3172176 displayed excellent test–retest reproducibility and is a highly promising ligand to quantify M1 receptors in the human brain.

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

11C-UCB-J is a PET tracer for synaptic vesicle glycoprotein 2A which may be a marker of synaptic density. To simplify the scan protocol, standardized uptake value ratios (SUVR) were compared to model-based binding potential (BPND) to select the optimal time window in healthy and neuropsychiatric subjects. Methods: A total of 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 BPND. 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 BPND is time-dependent. Conclusion: The 60-90 min period provided the best match between SUVR-1 and BPND (-1±7%), thus, a short scan is sufficient for accurate quantification of 11C-UCB-J specific binding.

The kappa opioid receptor (KOR) is implicated in various neuropsychiatric disorders. We previously evaluated an agonist tracer, 11C-GR103545, for PET imaging of KOR in humans. Although 11C-GR103545 showed high brain uptake, good binding specificity, and selectivity to KOR, it displayed slow kinetics and relatively large test-retest variability (TRV) of distribution volume (VT) estimates (15%). Therefore we set out to develop two novel KOR agonist radiotracers, 11C-EKAP and 11C-FEKAP, and in nonhuman primates, both tracers exhibited faster kinetics and comparable binding parameters to 11C-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 11C-EKAP and 11C-FEKAP. Metabolite-corrected arterial input functions were measured. Regional time-activity curves (TACs) were generated for 14 regions of interest. One- and two-tissue compartment models (1TC, 2TC) and the multilinear analysis-1 (MA1) method were applied to the regional TACs to calculate VT. Time-stability of VT values and test-retest reproducibility were evaluated. Levels of specific binding, as measured by the non-displaceable binding potential (BPND) for the three tracers (11C-EKAP, 11C-FEKAP and 11C-GR103545), were compared using a graphical method. Results: For both tracers, regional TACs were fitted well with the 2TC model and MA1 method (t*=20min), but not with the 1TC model. Given unreliably estimated parameters in several fits with the 2TC model and a good match between VT values from MA1 and 2TC, MA1 was chosen as the appropriate model for both tracers. Mean MA1 VT values were highest for 11C-GR103545, followed by 11C-EKAP, then 11C-FEKAP. Minimum scan time for stable VT measurement was 90 and 110min for 11C-EKAP and 11C-FEKAP, respectively, compared with 140min for 11C-GR103545. The mean absolute TRV in MA1 VT estimates was 7% and 18% for 11C-EKAP and 11C-FEKAP, respectively. BPND levels were similar for 11C-FEKAP and 11C-GR103545, but ~25% lower for 11C-EKAP. Conclusion: The two novel KOR agonist tracers showed faster tissue kinetics than 11C-GR103545. Even with slightly lower BPND, 11C-EKAP is judged to be a better tracer for imaging and quantification of KOR in humans, based on the shorter minimum scan time and excellent test-retest.

Synaptic vesicle glycoprotein 2A (SV2A) is a 12-pass transmembrane glycoprotein ubiquitously expressed in presynaptic vesicles. In vivo imaging of SV2A using PET has potential applications in the d...

In this monthly Kappan column, authors recommend books that have influenced and inspired them in their education careers. This month, David Labaree recommends Confessions of a School Reformer by Larry Cuban, and Nina Weisling and Wendy Gardiner recommend The Price of Nice: How Good Intentions Maintain Educational Inequality, edited by Angelina E. Castagno.

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

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 11C-AS2471907 (3-(2-chlorophenyl)-4-(methyl-11 C)-5-[2-[2,4,6-trifluorophenoxy]propan-2-yl]-4H-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 11C-AS2471907. Two subjects underwent an additional scan after blockade with the selective and high-affinity 11β-HSD1 inhibitor ASP3662 to evaluate 11C-AS2471907 nondisplaceable distribution volume. Five subjects also underwent an additional scan to evaluate the within-day test-retest variability of 11C-AS2471907 volumes of distribution (V T). Results: 11C-AS2471907 time-activity curves were best fitted by the 2-tissue-compartment (2TC) model. 11C-AS2471907 exhibited a regionally varying pattern of uptake throughout the brain. The V T of 11C-AS2471907 ranged from 3.7 ± 1.5 mL/cm3 in the caudate nucleus to 14.5 ± 5.3 mL/cm3 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/cm3 for 11C-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: 11C-AS2471907 has a high fraction of specific binding in vivo in humans and reasonable within-day reproducibility of binding parameters.

The M1 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’s disease and schizophrenia. The availability of M1-selective radiotracers for positron emission tomography (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 11C-LSN3172176 (ethyl 4-(6-(methyl-11C)-2-oxoindolin-1-yl)-[1,49-bipiperidine]-19-carboxylate) in non-human primates. Methods:11C-LSN3172176 was radiolabeled via the Suzuki-Miyaura cross-coupling method. PET scans in rhesus macaques were acquired on the Focus-220 for 2 h with arterial blood sampling and metabolite analysis to measure the input function. Blocking scans with scopolamine (50 µg/kg) and the M1-selective agent AZD6088 (0.67 and 2 mg/kg) were performed to assess tracer binding specificity and selectivity. Regional brain time-activity curves (TACs) were analyzed with the one-tissue (1T) compartment model and the multilinear analysis method (MA1) to calculate regional distribution volume (VT). Non-displaceable binding potential (BPND) values were calculated using the cerebellum as reference region. Results:11C-LSN3172176 was synthesized with >99% radiochemical purity and high molar activity. In rhesus monkeys 11C-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 1T and MA1 methods. MA1-derived VT values were high (range of 10-81 mL/cm3) in all known M1 mAChR-rich brain regions. Pre-treatment with scopolamine and AZD6088 significantly reduced the brain uptake of 11C-LSN3172176, thus demonstrating its binding specificity and selectivity in vivo. The cerebellum appeared to be a suitable reference region for derivation of BPND, which ranged from 2.42 in the globus pallidus to 8.48 in the nucleus accumbens. Conclusion:11C-LSN3172176 exhibits excellent in vivo binding and imaging characteristics in non-human primates and appears to be the first appropriate radiotracer for PET imaging of human M1 AChR.

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

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.

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.

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 (23M/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 – 0.63xBMI + 0.27xAge, 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.

(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.

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).

Previous studies demonstrated the utility of [18F]fluoropropyl-(+)-dihydrotetrabenazine ([18F]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 [18F]FP-(+)-DTBZ with the inactive enantiomer, [18F]FP-(−)-DTBZ. This was the first human study of [18F]FP-(−)-DTBZ. Six HCs and four T1DM patients were scanned on separate days after injection of [18F]FP-(+)-DTBZ or [18F]FP-(−)-DTBZ. Distribution volumes (VT) and standardized uptake values (SUVs) were compared between groups. Three methods for calculation of non-displaceable uptake (VND) or reference SUV were applied: (1) use of [18F]FP-(+)-DTBZ reference VT as VND, assuming VND is uniform across organs; (2) use of [18F]FP-(−)-DTBZ pancreatic VT as VND, assuming that VND is uniform between enantiomers in the pancreas; and (3) use of a scaled [18F]FP-(+)-DTBZ reference VT as VND, assuming that a ratio of non-displaceable uptake between organs is uniform between enantiomers. Group differences in VT (or SUV), binding potential (BPND), or SUV ratio (SUVR) were estimated using these three methods. [18F]FP-(−)-DTBZ VT values were different among organs, and VT(+) and VT(−) were also different in the renal cortex and spleen. Method 3 with the spleen to estimate VND (or reference SUV) gave the highest non-displaceable uptake and the largest HC vs. T1DM group differences. Significant group differences were also observed in VT (or SUV) with method 1 using spleen. SUV was affected by differences in the input function between groups and between enantiomers. Non-displaceable uptake was different among organs and between enantiomers. Use of scaled spleen VT values for VND is a suitable method for quantification of VMAT2 in the pancreas.

We report herein a modification to a component of the GE radiochemistry system that increases the yield and reliability of [11 C]CN- production from [11 C]carbon dioxide.

327 Objectives: Benign bone diseases and malignant bone lesions can have similar patterns of F-18 uptake in [F-18]NaF PET/CT imaging. This can make clinical evaluations challenging and inhibits the development of automated image analysis tools for bone scans. We evaluated the performance of a deep convolutional neural network for automatically differentiating benign and malignant lesions in NaF PET/CT images. Methods: Thirty-eight NaF PET/CT scans of patients with metastatic prostate cancer were evaluated by an experienced nuclear medicine physician. Evaluation consisted of identifying and scoring each bone lesion as (1) definitely benign, (2) likely benign, (3) equivocal, (4) likely malignant, and (5) definitely malignant. A subset of 14 scans was likewise evaluated by an additional 3 nuclear medicine physicians working independently, followed by a convened consensus among the physicians. Local 20 cm × 20 cm image patches centered on each lesion were extracted as inputs to a deep convolutional neural network, with each input patch consisting of 3 image channels: a maximum intensity projection (MIP) of the coronal PET, a MIP of the axial PET, and the axial CT. The network followed the VGG19 architecture, with 16 3×3 convolutional layers followed by 2 fully connected layers and a final softmax layer. The network’s weights were pre-trained using the ImageNet database of natural images, causing it to learn general image features. The network was then tuned using the lesion images and physician scores. The network’s accuracy (ACC), sensitivity (SEN), specificity (SPEC), and positive predictive values (PPV) were evaluated on an independent testing dataset comprising 30% of the data. Results: A total of 2,557 lesions were scored by one physician, 1,334 of which were also scored by the additional 3 physicians. When trained to differentiate benign (scores 1-2) and malignant (scores 4-5) lesions using the scores from a single physician, the network achieved an ACC, SEN, SPEC, and PPV of 0.82, 0.80, 0.84, and 0.88, respectively. When trained to predict the consensus scores of the physicians, the network’s performance worsened slightly to 0.86 (ACC), 0.73 (SEN), 0.86 (SPEC), and 0.82 (PPV). This reduction in performance is likely due to fewer training samples and imperfect agreement among physician scores. The network’s performance improved when trained to differentiate between definitely benign (score=1) and definitely malignant (score=5) lesions, with ACC, SEN, SPEC, and PPV of 0.88, 0.90, 0.85, and 0.90, respectively. Conclusions: Deep convolutional neural networks can be trained to accurately differentiate between benign and malignant bone lesions in NaF PET/CT images. Automatic classification of bone lesions may lead to improved clinical interpretation and facilitate the development of advanced image analysis tools for NaF PET/CT bone scans.

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 11C-labeled PET radiotracers for KOR imaging in humans. Here we report the synthesis and evaluation of 18F-LY2459989 as the first 18F-labeled KOR antagonist radiotracer in nonhuman primates and its comparison with 11C-LY2459989. Methods: The novel radioligand 18F-LY2459989 was synthesized by 18F 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, 18F-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, 18F-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 18F-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 18F-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 18F-LY2459989 and 11C-LY2459989 indicated similar kinetic and binding profiles for the 2 radiotracers. Taken together, the results indicated that 18F-LY2459989 appears to be an excellent PET radiotracer for the imaging and quantification of the KOR in vivo.

BACKGROUND: Electronic cigarettes (ECs) can influence nicotine addiction by delivering aerosolized nicotine. We investigated if nicotine from ECs is delivered to the brain β(2)*-nicotinic acetylcholine receptors (β(2)*-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 β(2)*-nAChR occupancy was higher after 36 mg/ml EC challenge compared to 8 mg/ml EC at trend level. Average β(2)*-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 β(2)*-nAChRs, we show that average β(2)*-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.

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.

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.

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 Kd 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 Kd. This method was applied in a study of healthy human subjects with the histamine H3 receptor radioligand [11C]GSK189254 to measure the PK-occupancy relationship of the H3 antagonist PF-03654746. From three test/retest studies, [11C]GSK189254 Kd 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 H3 binding sites ( ROmax = 100%), and its IC50 was estimated to be 0.144 ± 0.010 ng/mL. The uncorrected IC50 was 26% higher.

1. Unbound brain drug concentration (Cb,u), a valid surrogate of interstitial fluid drug concentration (CISF), cannot be directly determined in humans, which limits accurately defining the human Cb,u:Cp,u of investigational molecules. 2. For the H3R antagonist (1R,3R)-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-lmethyl)phenyl]cyclobutane-1-carboxamide (PF-03654746), we interrogated Cb,u:Cp,u in humans and nonhuman primate (NHP). 3. In rat, PF-03654746 achieved net blood–brain barrier (BBB) equilibrium (Cb,u:Cp,u of 2.11). 4. In NHP and humans, the PET receptor occupancy-based Cp,u IC50 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 H3 Ki (2.3 nM). 5. In an attempt to understand this higher-than-expected potency in humans and NHP, rat-derived Cb,u:Cp,u of PF-03654746 was integrated with Cp,u IC50 to identify unbound (neuro) potency of PF-03654746, nIC50. 6. The nIC50 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 H3 Ki (2.3 nM). 7. This correlation of the nIC50 and in vitro hH3 Ki suggested the translation of net BBB equilibrium of PF-03654746 from rat to NHP and humans, and confirmed the use of Cp,u as a reliable surrogate of Cb,u. 8. Thus, nIC50 quantitatively informed the human Cb,u:Cp,u of PF-03654746.

This was a first-in-human study of the novel phosphodiesterase-2A (PDE2A) PET ligand 18F-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: 18F-PF-05270430 shows promise as a PDE2A PET ligand, albeit with low binding potential values.

Positron emission tomography tracers [11C]ABP688 and [18F]FPEB target the metabotropic glutamate receptor subtype 5 providing quantification of the brain glutamatergic system in vivo. Previous [11C]ABP688 positron emission tomography human test–retest studies indicate that, when performed on the same day, significant binding increases are observed; however, little deviation is reported when scans are >7 days apart. Due to the small cohorts examined previously (eight and five males, respectively), we aimed to replicate the same-day test–retest studies in a larger cohort including both males and females. Results confirmed large within-subject binding differences (ranging from −23% to 108%), suggesting that measurements are greatly affected by study design. We further investigated whether this phenomenon was specific to [11C]ABP688. Using [18F]FPEB and methodology that accounts for residual radioactivity from the test scan, four subjects were scanned twice on the same day. In these subjects, binding estimates increased between 5% and 39% between scans. Consistent with [11C]ABP688, mean absolute test–retest variability was previously reported as 21 days apart. This replication study and pilot extension to [18F]FPEB suggest that observed within-day binding variation may be due to characteristics of mGluR5; for example, diurnal variation in mGluR5 may affect measurement of this receptor.

Development of medications selective for dopamine D2 or D3 receptors is an active area of research in numerous neuropsychiatric disorders including addiction and Parkinson’s disease. The positron emission tomography (PET) radiotracer [11C]-(+)-PHNO, an agonist that binds with high affinity to both D2 and D3 receptors, has been used to estimate relative receptor subtype occupancy by drugs based on a priori knowledge of regional variation in the expression of D2 and D3 receptors. The objective of this work was to use a data-driven independent component analysis (ICA) of receptor blocking scans to separate D2-and D3-related signal in [11C]-(+)-PHNO binding data in order to improve the precision of subtype specific measurements of binding and occupancy. Eight healthy volunteers underwent [11C]-(+)-PHNO PET scans at baseline and at two time points following administration of the D3-preferring antagonist ABT-728 (150–1000 ​mg). Parametric binding potential (BPND) images were analyzed as four-dimensional image series using ICA to extract two independent sources of variation in [11C]-(+)-PHNO BPND. Spatial source maps for each component were consistent with respective regional patterns of D2-and D3-related binding. ICA-derived occupancy estimates from each component were similar to D2-and D3-specific occupancy estimated from a region-based approach (intraclass correlation coefficients ​> ​0.95). ICA-derived estimates of D3 receptor occupancy improved quality of fit to a single site binding model. Furthermore, ICA-derived estimates of the regional fraction of [11C]-(+)-PHNO binding related to D3 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 D2-and D3-related components of the [11C]-(+)-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. Editor highlights: • ICA of [11C]-(+)-PHNO PET competition binding data with a D3-selective drug. • Produced individual maps of D2-and D3-receptor binding patterns. • More precise D3 occupancy and EC50 estimates compared to conventional methods. • ICA offers a data-driven method to separate signals from multi-target PET tracers.

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 (D2/3) 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 D2/3 receptor binding and stimulant-induced dopamine release using PET and [11C]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 [11C]raclopride before and after the administration of oral methylphenidate (60 mg) to measure D2/3 binding and dopamine release. Results There was no significant difference in the PET measures of D2/3 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 D2/3 receptor binding potential or methylphenidate-induced dopamine release relative to healthy controls.

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.

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

243 Objectives The objectives of this study was to identify prevalence of respiratory motion in dynamic PET myocardial perfusion images, its effects on myocardial blood flow (MBF) and coronary flow reserve (CFR) estimates and to investigate the implications of the weighting model deployed during kinetic fit to minimize effects of motion. Methods This study used 53 randomly selected patients referred for dynamic stress/rest Rb-82 PET imaging. Dynamic image series were iteratively reconstructed. The left ventricular (LV) blood pool and tissue time activity curves (TAC) were sampled using ROI and fit to a compartment model with uniform or tissue weighting for MBF and CFR quantification using Corridor4DM software (INVIA). Tissue weighting incorporated the frame duration, decay correction factor, and activity concentration. Motion was assessed visually from the dynamic series and categorized with having minimal, moderate, or severe motion. Studies with moderate or severe motion were manually corrected for comparison. Results Moderate and severe motion was observed in 46% and 39% of the studies respectively. Motion was most prominent in the blood pool phases with 55% of the motion in the craniocaudal direction. Compared to the motion corrected images, images with moderate motion had global stress MBF values 3.2% higher when uniform weighting was used. Using tissue weighting only reduced those differences by 0.5%. Studies with severe motion had greater stress MBF differences: 5.8% (uniform) and 5.4% (tissue). Regionally stress MBF values in the RCA varied the greatest: 20.2% (uniform) and 19.9% (tissue). Conclusions Respiratory motion is problematic in the blood pool phase due to fast kinetics of the tracer and the short time sampling. Increasing differences in MBF and CFR estimates were observed between studies with minimal, moderate, and severe motion. Tissue weighting has limited impact on reducing the increase in MBF and CFR estimates caused by motion suggesting motion correction is needed to reduce bias in flow estimates.

[11C]MP-10 is a potent and specific PET tracer previously shown to be suitable for imaging the phosphodiesterase 10A (PDE10A) in baboons with reversible kinetics and high specific binding. However, another report indicated that [11C]MP-10 displayed seemingly irreversible kinetics in rhesus monkeys, potentially due to the presence of a radiolabeled metabolite capable of penetrating the blood-brain-barrier (BBB) into the brain. This study was designed to address the discrepancies between the species by re-evaluating [11C]MP-10 in vivo in rhesus monkey with baseline scans to assess tissue uptake kinetics and self-blocking scans with unlabeled MP-10 to determine binding specificity. Ex vivo studies with one rhesus monkey and 4 Sprague-Dawley rats were also performed to investigate the presence of radiolabeled metabolites in the brain. Our results indicated that [11C]MP-10 displayed reversible uptake kinetics in rhesus monkeys, albeit slower than in baboons. Administration of unlabeled MP-10 reduced the binding of [11C]MP-10 in a dose-dependent manner in all brain regions including the cerebellum. Consequently, the cerebellum appeared not to be a suitable reference tissue in rhesus monkeys. Regional volume of distribution (VT) was mostly reliably derived with the multilinear analysis (MA1) method. In ex vivo studies in the monkey and rats only negligible amount of radiometabolites was seen in the brain of either species. In summary, results from the present study strongly support the suitability of [11C]MP-10 as a radiotracer for PET imaging and quantification of PDE10A in nonhuman primates. Synapse 69:86–95, 2015. © 2014 Wiley Periodicals, Inc.

Cigarette smoking is a major public health danger. Women and men smoke for different reasons and cessation treatments, such as the nicotine patch, are preferentially beneficial to men. The biological substrates of these sex differences are unknown. Earlier PET studies reported conflicting findings but were each hampered by experimental and/or analytical limitations. Our new image analysis technique, lp-ntPET (Normandin et al., 2012; Morris et al., 2013; Kim et al., 2014), has been optimized for capturing brief (lasting only minutes) and highly localized dopaminergic events in dynamic PET data. We coupled our analysis technique with high-resolution brain scanning and high-frequency motion correction to create the optimal experiment for capturing and characterizing the effects of smoking on the mesolimbic dopamine system in humans. Our main finding is that male smokers smoking in the PET scanner activate dopamine in the right ventral striatum during smoking but female smokers do not. This finding—men activating more ventrally than women—is consistent with the established notion that men smoke for the reinforcing drug effect of cigarettes whereas women smoke for other reasons, such as mood regulation and cue reactivity. lp-ntPET analysis produces a novel multidimensional endpoint: voxel-level temporal patterns of neurotransmitter release (“DA movies”) in individual subjects. By examining these endpoints quantitatively, we demonstrate that the timing of dopaminergic responses to cigarette smoking differs between men and women. Men respond consistently and rapidly in the ventral striatum whereas women respond faster in a discrete subregion of the dorsal putamen.

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

The α7 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 PET radioligands specific to α7 nAChRs, [18F]ASEM (3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-([18F]fluorodibenzo[b,d]thiophene 5,5-dioxide) and [18F]DBT-10 (7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-([18F]fluorodibenzo[b,d]thiophene 5,5-dioxide), in nonhuman primates. The second aim was to further assess the quantification and test-retest variability of [18F]ASEM in humans.