Evaluation of a First PET Tracer Suitable for Imaging the Sigma-2 Receptor in the Brain of Nonhuman Primates.

The sigma-2 receptor (σ2R), recently identified as transmembrane protein 97, is expressed in many cell types and mediates important functions in both the peripheral and central nervous systems. Over the years, σ2R has emerged as a potential therapeutic target for cancer and neurological disorders such as Alzheimer's disease (AD). The currently available σ2R radiotracers have been developed primarily for cancer imaging with limited brain uptake. Here, we report the evaluation of the first brain penetrant 18F-labeled radiotracer suitable for positron emission tomography (PET) imaging of σ2R in nonhuman primate brain.

Chronic GCPII (glutamate-carboxypeptidase-II) inhibition reduces pT217Tau levels in the entorhinal and dorsolateral prefrontal cortices of aged macaques.

Introduction: Current approaches for treating sporadic Alzheimer's disease (sAD) focus on removal of amyloid beta 1-42 (Aß1-42) or phosphorylated tau, but additional strategies are needed to reduce neuropathology at earlier stages prior to neuronal damage. Longstanding data show that calcium dysregulation is a key etiological factor in sAD, and the cortical neurons most vulnerable to tau pathology show magnified calcium signaling, for example in dorsolateral prefrontal cortex (dlPFC) and entorhinal cortex (ERC). In primate dlPFC and ERC, type 3 metabotropic glutamate receptors (mGluR3s) are predominately post-synaptic, on spines, where they regulate cAMP-calcium signaling, a process eroded by inflammatory glutamate carboxypeptidase II (GCPII) actions. The current study tested whether enhancing mGluR3 regulation of calcium via chronic inhibition of GCPII would reduce tau hyperphosphorylation in aged macaques with naturally-occurring tau pathology. Methods: Aged rhesus macaques were treated daily with the GCPII inhibitor, 2-MPPA (2-3-mercaptopropyl-penanedioic acid (2-MPPA)),Aged rhesus macaques were treated daily with the GCPII inhibitor, 2-MPPA (2-3-mercaptopropyl-penanedioic acid (2-MPPA)). Results: Aged macaques that received 2-MPPA had significantly lower pT217Tau levels in dlPFC and ERC, and had lowered plasma pT217Tau levels from baseline. pT217Tau levels correlated significantly with GCPII activity in dlPFC. Both 2-MPPA- and vehicle-treated monkeys showed cognitive improvement; 2-MPPA had no apparent side effects. Exploratory CSF analyses indicated reduced pS202Tau with 2-MPPA administration, confirmed in dlPFC samples. Discussion: These data provide proof-of-concept support that GCPII inhibition can reduce tau hyperphosphorylation in the primate cortices most vulnerable in sAD. GCPII inhibition may be particularly helpful in reducing the risk of sAD caused by inflammation. These data in nonhuman primates should encourage future research on this promising mechanism. Highlights: Inflammation is a key driver of sporadic Alzheimer's disease.GCPII inflammatory signaling in brain decreases mGluR3 regulation of calcium.Chronic inhibition of GCPII inflammatory signaling reduced pT217Tau in aged monkeys.GCPII inhibition is a novel strategy to help prevent tau pathology at early stages.

In Vivo Imaging and Kinetic Modeling of Novel Glycogen Synthase Kinase-3 Radiotracers [11C]OCM-44 and [18F]OCM-50 in Non-Human Primates.

Glycogen synthase kinase 3 (GSK-3) is a potential therapeutic target for a range of neurodegenerative and psychiatric disorders. The goal of this work was to evaluate two leading GSK-3 positron emission tomography (PET) radioligands, [11C]OCM-44 and [18F]OCM-50, in non-human primates to assess their potential for clinical translation. A total of nine PET scans were performed with the two radiotracers using arterial blood sampling in adult rhesus macaques. Brain regional time-activity curves were extracted and fitted with one- and two-tissue compartment models using metabolite-corrected arterial input functions. Target selectivity was assessed after pre-administration of the GSK-3 inhibitor PF-04802367 (PF-367, 0.03-0.25 mg/kg). Both radiotracers showed good brain uptake and distribution throughout grey matter. [11C]OCM-44 had a free fraction in the plasma of 3% at baseline and was metabolized quickly. The [11C]OCM-44 volume of distribution (VT) values in the brain increased with time; VT values from models fitted to truncated 60-min scan data were 1.4-2.9 mL/cm3 across brain regions. The plasma free fraction was 0.6% for [18F]OCM-50 and VT values (120-min) were 0.39-0.87 mL/cm3 in grey matter regions. After correcting for plasma free fraction increases during blocking scans, reductions in regional VT indicated >80% target occupancy by 0.1 mg/kg of PF-367 for both radiotracers, supporting target selectivity in vivo. [11C]OCM-44 and [18F]OCM-50 warrant further evaluation as radioligands for imaging GSK-3 in the brain, though radio-metabolite accumulation may confound image analysis.

Preclinical evaluation of a brain penetrant PARP PET imaging probe in rat glioblastoma and nonhuman primates.

PURPOSE: Currently, there are multiple active clinical trials involving poly(ADP-ribose) polymerase (PARP) inhibitors in the treatment of glioblastoma. The noninvasive quantification of baseline PARP expression using positron emission tomography (PET) may provide prognostic information and lead to more precise treatment. Due to the lack of brain-penetrant PARP imaging agents, the reliable and accurate in vivo quantification of PARP in the brain remains elusive. Herein, we report the synthesis of a brain-penetrant PARP PET tracer, (R)-2-(2-methyl-1-(methyl-11C)pyrrolidin-2-yl)-1H-benzo[d]imidazole-4-carboxamide ([11C]PyBic), and its preclinical evaluations in a syngeneic RG2 rat glioblastoma model and healthy nonhuman primates. METHODS: We synthesized [11C]PyBic using veliparib as the labeling precursor, performed dynamic PET scans on RG2 tumor-bearing rats and calculated the distribution volume ratio (DVR) using simplified reference region method 2 (SRTM2) with the contralateral nontumor brain region as the reference region. We performed biodistribution studies, western blot, and immunostaining studies to validate the in vivo PET quantification results. We characterized the brain kinetics and binding specificity of [11C]PyBic in nonhuman primates on FOCUS220 scanner and calculated the volume of distribution (VT), nondisplaceable volume of distribution (VND), and nondisplaceable binding potential (BPND) in selected brain regions. RESULTS: [11C]PyBic was synthesized efficiently in one step, with greater than 97% radiochemical and chemical purity and molar activity of 148 ± 85 MBq/nmol (n = 6). [11C]PyBic demonstrated PARP-specific binding in RG2 tumors, with 74% of tracer binding in tumors blocked by preinjected veliparib (i.v., 5 mg/kg). The in vivo PET imaging results were corroborated by ex vivo biodistribution, PARP1 immunohistochemistry and immunoblotting data. Furthermore, brain penetration of [11C]PyBic was confirmed by quantitative monkey brain PET, which showed high specific uptake (BPND > 3) and low nonspecific uptake (VND < 3 mL/cm3) in the monkey brain. CONCLUSION: [11C]PyBic is the first brain-penetrant PARP PET tracer validated in a rat glioblastoma model and healthy nonhuman primates. The brain kinetics of [11C]PyBic are suitable for noninvasive quantification of available PARP binding in the brain, which posits [11C]PyBic to have broad applications in oncology and neuroimaging.

Reversal of synapse loss in Alzheimer mouse models by targeting mGluR5 to prevent synaptic tagging by C1Q.

Microglia-mediated synaptic loss contributes to the development of cognitive impairments in Alzheimer's disease (AD). However, the basis for this immune-mediated attack on synapses remains to be elucidated. Treatment with the metabotropic glutamate receptor 5 (mGluR5) silent allosteric modulator (SAM), BMS-984923, prevents ß-amyloid oligomer-induced aberrant synaptic signaling while preserving physiological glutamate response. Here, we show that oral BMS-984923 effectively occupies brain mGluR5 sites visualized by [18F]FPEB positron emission tomography (PET) at doses shown to be safe in rodents and nonhuman primates. In aged mouse models of AD (APPswe/PS1ΔE9 overexpressing transgenic and AppNL-G-F/hMapt double knock-in), SAM treatment fully restored synaptic density as measured by [18F]SynVesT-1 PET for SV2A and by histology, and the therapeutic benefit persisted after drug washout. Phospho-TAU accumulation in double knock-in mice was also reduced by SAM treatment. Single-nuclei transcriptomics demonstrated that SAM treatment in both models normalized expression patterns to a far greater extent in neurons than glia. Last, treatment prevented synaptic localization of the complement component C1Q and synaptic engulfment in AD mice. Thus, selective modulation of mGluR5 reversed neuronal gene expression changes to protect synapses from damage by microglial mediators in rodents.

Comparison of three novel radiotracers for GluN2B-containing NMDA receptors in non-human primates: (R)-[11C]NR2B-Me, (R)-[18F]of-Me-NB1, and (S)-[18F]of-NB1.

The NMDA receptor GluN2B subunit is a target of interest in neuropsychiatric disorders but to date there is no selective radiotracer available to quantify its availability in vivo. Here we report direct comparisons in non-human primates of three GluN2B-targeting radioligands: (R)-[11C]NR2B-Me, (R)-[18F]OF-Me-NB1, and (S)-[18F]OF-NB1. Plasma free fraction, metabolism, tissue distribution and kinetics, and quantitative kinetic modeling methods and parameters were evaluated in two adult rhesus macaques. Free fraction in plasma was <2% for (R)-[11C]NR2B-Me and (R)-[18F]OF-Me-NB1 and higher for (S)-[18F]OF-NB1 (15%). All radiotracers showed good brain uptake and distribution throughout grey matter, with substantial (>68%) blockade across the brain by the GluN2B-targeting drug Co-101,244 (0.25 mg/kg), including in the cerebellum. Time-activity curves were well-fitted by the one-tissue compartment model, with volume of distribution values of 20-40 mL/cm3 for (R)-[11C]NR2B-Me, 8-16 mL/cm3 for (R)-[18F]OF-Me-NB1, and 15-35 mL/cm3 for (S)-[18F]OF-NB1. Estimates of regional non-displaceable binding potential were in the range of 2-3 for (R)-[11C]NR2B-Me and (S)-[18F]-OF-NB1, and 0.5-1 for (R)-[18F]OF-Me-NB1. Altogether, each radiotracer showed an acceptable profile for quantitative imaging of GluN2B. (S)-[18F]OF-NB1 has particularly promising imaging characteristics for potential translation into humans. However, the source of unexpected displaceable binding in the cerebellum for each of these compounds requires further investigation.

Characterization in nonhuman primates of (R)-[18F]OF-Me-NB1 and (S)-[18F]OF-Me-NB1 for imaging the GluN2B subunits of the NMDA receptor.

PURPOSE: GluN2B containing N-methyl-D-aspartate receptors (NMDARs) play an essential role in neurotransmission and are a potential treatment target for multiple neurological and neurodegenerative diseases, including stroke, Alzheimer's disease, and Parkinson's disease. (R)-[18F]OF-Me-NB1 was reported to be more specific and selective than (S)-[18F]OF-Me-NB1 for the GluN2B subunits of the NMDAR based on their binding affinity to GluN2B and sigma-1 receptors. Here we report a comprehensive evaluation of (R)-[18F]OF-Me-NB1 and (S)-[18F]OF-Me-NB1 in nonhuman primates. METHODS: The radiosynthesis of (R)-[18F]OF-Me-NB1 and (S)-[18F]OF-Me-NB1 started from 18F-fluorination of the boronic ester precursor, followed by removal of the acetyl protecting group. PET scans in two rhesus monkeys were conducted on the Focus 220 scanner. Blocking studies were performed after treatment of the animals with the GluN2B antagonist Co101,244 or the sigma-1 receptor antagonist FTC-146. One-tissue compartment (1TC) model and multilinear analysis-1 (MA1) method with arterial input function were used to obtain the regional volume of distribution (VT, mL/cm3). Occupancy values by the two blockers were obtained by the Lassen plot. Regional non-displaceable binding potential (BPND) was calculated from the corresponding baseline VT and the VND derived from the occupancy plot of the Co101,244 blocking scans. RESULTS: (R)- and (S)-[18F]OF-Me-NB1 were produced in > 99% radiochemical and enantiomeric purity, with molar activity of 224.22 ± 161.69 MBq/nmol at the end of synthesis (n = 10). Metabolism was moderate, with ~ 30% parent compound remaining for (R)-[18F]OF-Me-NB1 and 20% for (S)-[18F]OF-Me-NB1 at 30 min postinjection. Plasma free fraction was 1-2%. In brain regions, both (R)- and (S)-[18F]OF-Me-NB1 displayed fast uptake with slower clearance for the (R)- than (S)-enantiomer. For (R)-[18F]OF-Me-NB1, both the 1TC model and MA1 method gave reliable estimates of regional VT values, with MA1 VT (mL/cm3) values ranging from 8.9 in the cerebellum to 12.8 in the cingulate cortex. Blocking with 0.25 mg/kg of Co101,244 greatly reduced the uptake of (R)-[18F]OF-Me-NB1 across all brain regions, resulting in occupancy of 77% and VND of 6.36, while 0.027 mg/kg of FTC-146 reduced specific binding by 30%. Regional BPND, as a measure of specific binding signals, ranged from 0.40 in the cerebellum to 1.01 in the cingulate cortex. CONCLUSIONS: In rhesus monkeys, (R)-[18F]OF-Me-NB1 exhibited fast kinetics and heterogeneous uptake across brain regions, while the (S)-enantiomer displayed a narrower dynamic range of uptake across regions. A Blocking study with a GluN2B antagonist indicated binding specificity. The value of BPND was > 0.5 in most brain regions, suggesting good in vivo specific binding signals. Taken together, results from the current study demonstrated the potential of (R)-[18F]OF-Me-NB1 as a useful radiotracer for imaging the GluN2B receptors.

Imaging the effect of ketamine on synaptic density (SV2A) in the living brain.

The discovery of ketamine as a rapid and robust antidepressant marks the beginning of a new era in the treatment of psychiatric disorders. Ketamine is thought to produce rapid and sustained antidepressant effects through restoration of lost synaptic connections. We investigated this hypothesis in humans for the first time using positron emission tomography (PET) and [11C]UCB-J-a radioligand that binds to the synaptic vesicle protein 2A (SV2A) and provides an index of axon terminal density. Overall, we did not find evidence of a measurable effect on SV2A density 24 h after a single administration of ketamine in non-human primates, healthy controls (HCs), or individuals with major depressive disorder (MDD) and/or posttraumatic stress disorder (PTSD), despite a robust reduction in symptoms. A post-hoc, exploratory analysis suggests that patients with lower SV2A density at baseline may exhibit increased SV2A density 24 h after ketamine. This increase in SV2A was associated with a reduction in depression severity, as well as an increase in dissociative symptoms. These initial findings suggest that a restoration of synaptic connections in patients with lower SV2A at baseline may underlie ketamine's therapeutic effects, however, this needs replication in a larger sample. Further work is needed to build on these initial findings and further establish the nuanced pre- and post-synaptic mechanisms underpinning ketamine's therapeutic effects.

A metabolically stable PET tracer for imaging synaptic vesicle protein 2A: synthesis and preclinical characterization of [18F]SDM-16.

PURPOSE: To quantify the synaptic vesicle glycoprotein 2A (SV2A) changes in the whole central nervous system (CNS) under pathophysiological conditions, a high affinity SV2A PET radiotracer with improved in vivo stability is desirable to minimize the potential confounding effect of radiometabolites. The aim of this study was to develop such a PET tracer based on the molecular scaffold of UCB-A, and evaluate its pharmacokinetics, in vivo stability, specific binding, and nonspecific binding signals in nonhuman primate brains, in comparison with [11C]UCB-A, [11C]UCB-J, and [18F]SynVesT-1. METHODS: The racemic SDM-16 (4-(3,5-difluorophenyl)-1-((2-methyl-1H-imidazol-1-yl)methyl)pyrrolidin-2-one) and its two enantiomers were synthesized and assayed for in vitro binding affinities to human SV2A. We synthesized the enantiopure [18F]SDM-16 using the corresponding enantiopure arylstannane precursor. Nonhuman primate brain PET scans were performed on FOCUS 220 scanners. Arterial blood was drawn for the measurement of plasma free fraction (fP), radiometabolite analysis, and construction of the plasma input function. Regional time-activity curves (TACs) were fitted with the one-tissue compartment (1TC) model to obtain the volume of distribution (VT). Nondisplaceable binding potential (BPND) was calculated using either the nondisplaceable volume of distribution (VND) or the centrum semiovale (CS) as the reference region. RESULTS: SDM-16 was synthesized in 3 steps with 44% overall yield and has the highest affinity (Ki = 0.9 nM) to human SV2A among all reported SV2A ligands. [18F]SDM-16 was prepared in about 20% decay-corrected radiochemical yield within 90 min, with greater than 99% radiochemical and enantiomeric purity. This radiotracer displayed high specific binding in monkey brains and was metabolically more stable than the other SV2A PET tracers. The fP of [18F]SDM-16 was 69%, which was higher than those of [11C]UCB-J (46%), [18F]SynVesT-1 (43%), [18F]SynVesT-2 (41%), and [18F]UCB-H (43%). The TACs were well described with the 1TC. The averaged test-retest variability (TRV) was 7 ± 3%, and averaged absolute TRV (aTRV) was 14 ± 7% for the analyzed brain regions. CONCLUSION: We have successfully synthesized a novel SV2A PET tracer [18F]SDM-16, which has the highest SV2A binding affinity and metabolical stability among published SV2A PET tracers. The [18F]SDM-16 brain PET images showed superb contrast between gray matter and white matter. Moreover, [18F]SDM-16 showed high specific and reversible binding in the NHP brains, allowing for the reliable and sensitive quantification of SV2A, and has potential applications in the visualization and quantification of SV2A beyond the brain.

The aerodynamics of flying snake airfoils in tandem configuration.

Flying snakes flatten their body to form a roughly triangular cross-sectional shape, enabling lift production and horizontal acceleration. While gliding, they also assume an S-shaped posture, which could promote aerodynamic interactions between the fore and the aft body. Such interactions have been studied experimentally; however, very coarse models of the snake's cross-sectional shape were used, and the effects were measured only for the downstream model. In this study, the aerodynamic interactions resulting from the snake's posture were approximated using two-dimensional anatomically accurate airfoils positioned in tandem to mimic the snake's geometry during flight. Load cells were used to measure the lift and drag forces, and flow field data were obtained using digital particle image velocimetry (DPIV). The results showed a strong dependence of the aerodynamic performance on the tandem arrangement, with the lift coefficients being generally more influenced than the drag coefficients. Flow field data revealed that the tandem arrangement modified the separated flow and the wake size, and enhanced the lift in cases in which the wake vortices formed closer to the models, producing suction on the dorsal surface. The downforce created by the flow separation from the ventral surface of the models at 0 deg angle of attack was another significant factor contributing to lift production. A number of cases showing large variations of aerodynamic performance included configurations close to the most probable posture of airborne flying snakes, suggesting that small postural variations could be used to control the glide trajectory.

Assessment of test-retest reproducibility of [18F]SynVesT-1, a novel radiotracer for PET imaging of synaptic vesicle glycoprotein 2A.

PURPOSE: Synaptic abnormalities are associated with many brain disorders. Recently, we developed a novel synaptic vesicle glycoprotein 2A (SV2A) radiotracer [18F]SynVesT-1 and demonstrated its excellent imaging and binding properties in nonhuman primates. The aim of this study was to perform dosimetry calculations in nonhuman primates and to evaluate this tracer in humans and assess its test-retest reliability in comparison with [11C]UCB-J. METHODS: Three rhesus monkeys underwent whole body dynamic PET scanning to estimate the absorbed dose. PET scans in six healthy human subjects were acquired. Time-activity curves (TACs) were generated with defined regions of interest (ROI). Reproducibility of distribution volume (VT) values and its sensitivity to scan duration were assessed with the one-tissue compartment (1TC) model. Non-displaceable binding potential (BPND) was calculated using centrum semiovale as the reference region. RESULTS: The dosimetry study showed high uptake in the urinary bladder and brain. In humans, [18F]SynVesT-1 displayed high uptake with maximum SUV of ~10 and appropriate kinetics with a quick rise in tracer uptake followed by a gradual clearance. Mean 1TC VT values (mL/cm3) ranged from 3.4 (centrum semiovale) to 19.6 (putamen) and were similar to those of [11C]UCB-J. Regional BPND values were 2.7-4.7 in gray matter areas, and mean BPND values across all ROIs were ~ 21% higher than those of [11C]UCB-J. The absolute test-retest variability of VT and BPND was excellent (< 9%) across all brain regions. CONCLUSIONS: [18F]SynVesT-1 demonstrates outstanding characteristics in humans: fast and high brain uptake, appropriate tissue kinetics, high levels of specific binding, and excellent test-retest reproducibility of binding parameters. As such, [18F]SynVesT-1 is proved to be a favorable radiotracer for SV2A imaging and quantification in humans.

The rate of dasotraline brain entry is slow following intravenous administration.

RATIONALE: Drugs that rapidly increase dopamine levels have an increased risk of abuse. Dasotraline (DAS) is a dopamine and norepinephrine reuptake inhibitor characterized by slow oral absorption with low potential for abuse. However, it remains unclear whether intravenous (i.v.) administration would facilitate the rapid elevation of dopamine levels associated with stimulant drugs. OBJECTIVE: To assess the kinetics of DAS across the blood-brain barrier and time to onset of dopamine transporters (DAT) inhibition. METHODS: We compared the onset of DAT occupancy and the associated elevation of synaptic dopamine levels in rhesus monkey following i.v. administration of DAS or methylphenidate (MPH) using positron emission tomography (PET). Brain entry times were estimated by reductions in [18F]-FE-PE2I binding to DAT in rhesus monkeys. Elevations of synaptic dopamine were estimated by reductions in [11C]-Raclopride binding to D2 receptors. RESULTS: Intravenous administration of DAS (0.1 and 0.2 mg/kg) resulted in striatal DAT occupancies of 54% and 68%, respectively; i.v. administered MPH (0.1 and 0.5 mg/kg) achieved occupancies of 69% and 88% respectively. Brain entry times of DAS (22 and 15 min, respectively) were longer than for MPH (3 and 2 min). Elevations in synaptic dopamine were similar for both DAS and MPH however the time for half-maximal displacement by MPH (t = 23 min) was 4-fold more rapid than for DAS (t = 88 min). CONCLUSIONS: These results demonstrate that the pharmacodynamics effects of DAS on DAT occupancy and synaptic dopamine levels are more gradual in onset than those of MPH even with i.v. administration that is favored by recreational drug abusers.

Dysregulation of Decision Making Related to Metabotropic Glutamate 5, but Not Midbrain D3, Receptor Availability Following Cocaine Self-administration in Rats.

BACKGROUND: Compulsive patterns of drug use are thought to be the consequence of drug-induced adaptations in the neural mechanisms that enable behavior to be flexible. Neuroimaging studies have found evidence of robust alterations in glutamate and dopamine receptors within brain regions that are known to be critical for decision-making processes in cocaine-dependent individuals, and these changes have been argued to be the consequence of persistent drug use. The causal relationships among drug-induced alterations, cocaine taking, and maladaptive decision-making processes, however, are difficult to establish in humans. METHODS: We assessed decision making in adult male rats using a probabilistic reversal learning task and used positron emission tomography with the [11C]-(+)-PHNO and [18F]FPEB radioligands to quantify regional dopamine D2/3 and metabotropic glutamate 5 (mGlu5) receptor availability, respectively, before and after 21 days of cocaine or saline self-administration. Tests of motivation and relapse-like behaviors were also conducted. RESULTS: We found that self-administration of cocaine, but not of saline, disrupted behavior in the probabilistic reversal learning task measured by selective impairments in negative-outcome updating and also increased cortical mGlu5 receptor availability following 2 weeks of forced abstinence. D2/3 and, importantly, midbrain D3 receptor availability was not altered following 2 weeks of abstinence from cocaine. Notably, the degree of the cocaine-induced increase in cortical mGlu5 receptor availability was related to the degree of disruption in negative-outcome updating. CONCLUSIONS: These findings suggest that cocaine-induced changes in mGlu5 signaling may be a mechanism by which disruptions in negative-outcome updating emerge in cocaine-dependent individuals.

Human adult and adolescent biodistribution and dosimetry of the synaptic vesicle glycoprotein 2A radioligand 11C-UCB-J.

The ability to quantify synaptic density in vivo in human adults and adolescents is of vital importance to understanding neuropsychiatric disorders. Here, we performed whole-body scans to determine organ radiation dosimetry of 11C-UCB-J in humans. METHODS: Dynamic whole-body PET scans were performed in four healthy adults after injection of 11C-UCB-J. Regions of interest (ROIs) were drawn manually for the brain, heart, stomach, kidneys, liver, pancreas, spleen, gallbladder, lungs, urinary bladder, and intestines. ROIs were applied to dynamic images to generate time-activity curves (TACs). Decay correction was removed from TACs, and the area under the curve (AUC) for each ROI was calculated. AUCs were then normalized by injected activity and organ volumes to produce radioligand residence times for each organ. These times were then used as input into the OLINDA/EXM 1.0 software to determine the total radiation dose in each organ and the effective dose for these OLINDA models: 55-kg female, 70-kg male, and 15-year-old adolescent. RESULTS: Visual evaluation detected high uptake in the liver, brain, gallbladder, gastrointestinal tract, and urinary bladder. The dose-limiting organ was the urinary bladder for adult males (0.0224 mSv/MBq) and liver for adult females (0.0248 mSv/MBq) with single-study dose limits of 2239 MBq and 2017 MBq 11C-UCB-J, respectively. For adolescents, the large intestine was the dose-limiting organ (0.0266 mSv/MBq) with a single-study dose limit of 188 MBq. CONCLUSIONS: 11C-UCB-J dosimetry in adults is consistent with those for many carbon-11-labeled ligands. Overall, 11C-UCB-J can be used safely in adolescents, as in adults, to measure synaptic density in various neuropsychiatric and other relevant disorders.

Positron Emission Tomography Imaging Evaluation of a Novel 18F-Labeled Sigma-1 Receptor Radioligand in Cynomolgus Monkeys.

We report a convenient radiosynthesis and the first positron emission tomography (PET) imaging evaluation of [18F]FBFP as a potent sigma-1 (σ1) receptor radioligand with advantageous characteristics. [18F]FBFP was synthesized in one step from an iodonium ylide precursor. In cynomolgus monkeys, [18F]FBFP displayed high brain uptake and suitable tissue kinetics for quantitative analysis. It exhibited heterogeneous distribution with higher regional volume of distribution (VT) values in the amygdala, hippocampus, insula, and frontal cortex. Pretreatment with the σ1 receptor agonist SA4503 (0.5 mg/kg) significantly reduced radioligand uptake in the monkey brain (>95%), indicating high binding specificity of [18F]FBFP in vivo. Compared with (S)-[18F]fluspidine, [18F]FBFP possessed higher regional nondisplaceable binding potential (BPND) values across the brain regions. These findings demonstrate that [18F]FBFP is a highly promising PET radioligand for imaging and quantification of σ1 receptors in humans.

Midbrain D3 Receptor Availability Predicts Escalation in Cocaine Self-administration.

BACKGROUND: Results from neuroimaging studies suggest that disruptions in flexible decision-making functions in substance-dependent individuals are a consequence of drug-induced neural adaptations. In addicted populations, however, the causal relationship between biobehavioral phenotypes of susceptibility and addiction consequence is difficult to dissociate. Indeed, evidence from animals suggests that poor decision making due to preexisting biological factors can independently enhance the risk for developing addiction-like behaviors. Neuroimaging studies in animals provide a unique translational approach for the identification of the neurobiological mechanisms that mediate susceptibility to addiction. METHODS: We used positron emission tomography in rats to quantify regional dopamine D2/3 receptors and metabotropic glutamate receptor 5 (mGluR5) and assessed decision making using a probabilistic reversal learning task. Susceptibility to self-administer cocaine was then quantified for 21 days followed by tests of motivation and relapse-like behaviors. RESULTS: We found that deficits specifically in reward-guided choice behavior on the probabilistic reversal learning task predicted greater escalation of cocaine self-administration behavior and greater motivation for cocaine and, critically, were associated with higher midbrain D3 receptor availability. Additionally, individual differences in midbrain D3 receptor availability independently predicted the rate of escalation in cocaine-taking behaviors. No differences in mGluR5 availability, responses during tests of extinction, or cue-induced reinstatement were observed between the groups. CONCLUSIONS: These findings indicate that our identified D3-mediated decision-making phenotype can be used as a behavioral biomarker for assessment of cocaine use susceptibility in human populations.

Synthesis and Preclinical Evaluation of an 18F-Labeled Synaptic Vesicle Glycoprotein 2A PET Imaging Probe: [18F]SynVesT-2.

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 diagnosis and prognosis of a variety of neuropsychiatric diseases, e.g., Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, autism, epilepsy, stroke, traumatic brain injury, post-traumatic stress disorder, depression, etc. Herein, we report the synthesis and evaluation of a new 18F-labeled SV2A PET imaging probe, [18F]SynVesT-2, which possesses fast in vivo binding kinetics and high specific binding signals in non-human primate brain.

Barely porous organic cages for hydrogen isotope separation.

The separation of hydrogen isotopes for applications such as nuclear fusion is a major challenge. Current technologies are energy intensive and inefficient. Nanoporous materials have the potential to separate hydrogen isotopes by kinetic quantum sieving, but high separation selectivity tends to correlate with low adsorption capacity, which can prohibit process scale-up. In this study, we use organic synthesis to modify the internal cavities of cage molecules to produce hybrid materials that are excellent quantum sieves. By combining small-pore and large-pore cages together in a single solid, we produce a material with optimal separation performance that combines an excellent deuterium/hydrogen selectivity (8.0) with a high deuterium uptake (4.7 millimoles per gram).

Anti-edema and antioxidant combination therapy for ischemic stroke via glyburide-loaded betulinic acid nanoparticles.

Stroke is a deadly disease without effective pharmacotherapies, which is due to two major reasons. First, most therapeutics cannot efficiently penetrate the brain. Second, single agent pharmacotherapy may be insufficient and effective treatment of stroke requires targeting multiple complementary targets. Here, we set to develop single component, multifunctional nanoparticles (NPs) for targeted delivery of glyburide to the brain for stroke treatment. Methods: To characterize the brain penetrability, we radiolabeled glyburide, intravenously administered it to stroke- bearing mice, and determined its accumulation in the brain using positron emission tomography-computed tomography (PET/CT). To identify functional nanomaterials to improve drug delivery to the brain, we developed a chemical extraction approach and tested it for isolation of nanomaterials from E. ulmoides, a medicinal herb. To assess the therapeutic benefits, we synthesized glyburide-loaded NPs and evaluated them in stroke- bearing mice. Results: We found that glyburide has a limited ability to penetrate the ischemic brain. We identified betulinic acid (BA) capable of forming NPs, which, after intravenous administration, efficiently penetrate the brain and significantly reduce ischemia-induced infarction as an antioxidant agent. We demonstrated that BA NPs enhance delivery of glyburide, leading to therapeutic benefits significantly greater than those achieved by either glyburide or BA NPs. Conclusion: This study suggests a new direction to identify functional nanomaterials and a simple approach to achieving anti-edema and antioxidant combination therapy. The resulting glyburide- loaded BA NPs may be translated into clinical applications to improve clinical management of stroke.

NMR relaxation and modelling study of the dynamics of SF6 and Xe in porous organic cages.

The porous solid formed from organic CC3 cage molecules has exceptional performance for rare gas separation. NMR spectroscopy provides a way to reveal the dynamical details by using experimental relaxation and diffusion measurements. Here, we investigated T1 and T2 relaxation as well as diffusion of 129Xe and SF6 gases in the CC3-R molecular crystal at various temperatures and magnetic field strengths. Advanced relaxation modelling made it possible to extract various important dynamical parameters for gases in CC3-R, such as exchange rates, activation energies and mobility rates of xenon, occupancies of the cavities, rotational correlational times, effective relaxation rates, and diffusion coefficients of SF6.