Publications by authors named "Daniel Holden"

49 Publications

The aerodynamics of flying snake airfoils in tandem configuration.

J Exp Biol 2021 Jul 23;224(14). Epub 2021 Jul 23.

Department of Biomedical Engineering and Mechanics, Virginia Tech, Blacksburg, VA 24061, USA.

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.
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http://dx.doi.org/10.1242/jeb.233635DOI Listing
July 2021

The aerodynamics of flying snake airfoils in tandem configuration.

J Exp Biol 2021 Jun 7. Epub 2021 Jun 7.

Department of Biomedical Engineering and Mechanics, Virginia Tech, USA.

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 (PIV). 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° 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.
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http://dx.doi.org/10.1242/jeb.233635DOI Listing
June 2021

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

Eur J Nucl Med Mol Imaging 2021 05 8;48(5):1327-1338. Epub 2021 Jan 8.

PET Center, Yale University School of Medicine, PO Box 208048, New Haven, CT, 06520-8048, USA.

Purpose: Synaptic abnormalities are associated with many brain disorders. Recently, we developed a novel synaptic vesicle glycoprotein 2A (SV2A) radiotracer [F]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 [C]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 (V) values and its sensitivity to scan duration were assessed with the one-tissue compartment (1TC) model. Non-displaceable binding potential (BP) was calculated using centrum semiovale as the reference region.

Results: The dosimetry study showed high uptake in the urinary bladder and brain. In humans, [F]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 V values (mL/cm) ranged from 3.4 (centrum semiovale) to 19.6 (putamen) and were similar to those of [C]UCB-J. Regional BP values were 2.7-4.7 in gray matter areas, and mean BP values across all ROIs were ~ 21% higher than those of [C]UCB-J. The absolute test-retest variability of V and BP was excellent (< 9%) across all brain regions.

Conclusions: [F]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, [F]SynVesT-1 is proved to be a favorable radiotracer for SV2A imaging and quantification in humans.
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http://dx.doi.org/10.1007/s00259-020-05149-3DOI Listing
May 2021

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

Biol Psychiatry 2020 11 29;88(10):777-787. Epub 2020 Jun 29.

Department of Psychiatry, Yale University, New Haven, Connecticut; Department of Neuroscience, Yale University, New Haven, Connecticut. Electronic address:

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 [C]-(+)-PHNO and [F]FPEB radioligands to quantify regional dopamine D 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. D and, importantly, midbrain D 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.
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http://dx.doi.org/10.1016/j.biopsych.2020.06.020DOI Listing
November 2020

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

Psychopharmacology (Berl) 2020 Nov 19;237(11):3435-3446. Epub 2020 Aug 19.

Sunovion Pharmaceuticals Inc., 84 Waterford Dr, Marlborough, MA, 01752, USA.

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 [F]-FE-PE2I binding to DAT in rhesus monkeys. Elevations of synaptic dopamine were estimated by reductions in [C]-Raclopride binding to D 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.
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http://dx.doi.org/10.1007/s00213-020-05623-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7651685PMC
November 2020

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

EJNMMI Res 2020 Jul 14;10(1):83. Epub 2020 Jul 14.

Yale PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 801 Howard Avenue, PO Box 208048, New Haven, CT, USA.

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 C-UCB-J in humans.

Methods: Dynamic whole-body PET scans were performed in four healthy adults after injection of C-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 C-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: C-UCB-J dosimetry in adults is consistent with those for many carbon-11-labeled ligands. Overall, C-UCB-J can be used safely in adolescents, as in adults, to measure synaptic density in various neuropsychiatric and other relevant disorders.
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http://dx.doi.org/10.1186/s13550-020-00670-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359974PMC
July 2020

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

ACS Chem Neurosci 2020 06 20;11(11):1673-1681. Epub 2020 May 20.

Yale PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut 06520, United States.

We report a convenient radiosynthesis and the first positron emission tomography (PET) imaging evaluation of [F]FBFP as a potent sigma-1 (σ) receptor radioligand with advantageous characteristics. [F]FBFP was synthesized in one step from an iodonium ylide precursor. In cynomolgus monkeys, [F]FBFP displayed high brain uptake and suitable tissue kinetics for quantitative analysis. It exhibited heterogeneous distribution with higher regional volume of distribution () values in the amygdala, hippocampus, insula, and frontal cortex. Pretreatment with the σ receptor agonist SA4503 (0.5 mg/kg) significantly reduced radioligand uptake in the monkey brain (>95%), indicating high binding specificity of [F]FBFP . Compared with ()-[F]fluspidine, [F]FBFP possessed higher regional nondisplaceable binding potential () values across the brain regions. These findings demonstrate that [F]FBFP is a highly promising PET radioligand for imaging and quantification of σ receptors in humans.
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http://dx.doi.org/10.1021/acschemneuro.0c00171DOI Listing
June 2020

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

Biol Psychiatry 2020 11 27;88(10):767-776. Epub 2020 Feb 27.

Department of Psychiatry, Yale University, New Haven, Connecticut; Department of Neuroscience, Yale University, New Haven, Connecticut. Electronic address:

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 D 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 D receptor availability. Additionally, individual differences in midbrain D 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 D-mediated decision-making phenotype can be used as a behavioral biomarker for assessment of cocaine use susceptibility in human populations.
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http://dx.doi.org/10.1016/j.biopsych.2020.02.017DOI Listing
November 2020

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

ACS Chem Neurosci 2020 02 4;11(4):592-603. Epub 2020 Feb 4.

PET Center, Department of Radiology and Biomedical Imaging , Yale University , New Haven , Connecticut 06520 , United States.

Synaptic vesicle glycoprotein 2A (SV2A) is a 12-pass transmembrane glycoprotein ubiquitously expressed in presynaptic vesicles. 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 F-labeled SV2A PET imaging probe, [F]SynVesT-2, which possesses fast binding kinetics and high specific binding signals in non-human primate brain.
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http://dx.doi.org/10.1021/acschemneuro.9b00618DOI Listing
February 2020

Barely porous organic cages for hydrogen isotope separation.

Science 2019 11;366(6465):613-620

Materials Innovation Factory and Department of Chemistry, University of Liverpool, 51 Oxford Street, Liverpool, L7 3NY, UK.

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).
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http://dx.doi.org/10.1126/science.aax7427DOI Listing
November 2019

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

Phys Chem Chem Phys 2019 Nov 30;21(44):24373-24382. Epub 2019 Oct 30.

NMR Research Unit, University of Oulu, P. O. Box 3000, 90014 Oulu, Finland.

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 T and T relaxation as well as diffusion of Xe and SF 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 SF.
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http://dx.doi.org/10.1039/c9cp04379aDOI Listing
November 2019

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

Theranostics 2019 21;9(23):6991-7002. Epub 2019 Sep 21.

Department of Neurosurgery, Yale University, New Haven, CT, 06510, USA.

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. 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 , a medicinal herb. To assess the therapeutic benefits, we synthesized glyburide-loaded NPs and evaluated them in stroke- bearing mice. 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. 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.
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http://dx.doi.org/10.7150/thno.35791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815966PMC
October 2020

Synthesis and in vivo evaluation of [F]UCB-J for PET imaging of synaptic vesicle glycoprotein 2A (SV2A).

Eur J Nucl Med Mol Imaging 2019 Aug 7;46(9):1952-1965. Epub 2019 Jun 7.

PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, 06520, USA.

Purpose: Synaptic abnormalities have been implicated in a variety of neuropsychiatric disorders, including epilepsy, Alzheimer's disease, and schizophrenia. Hence, PET imaging of the synaptic vesicle glycoprotein 2A (SV2A) may be a valuable in vivo biomarker for neurologic and psychiatric diseases. We previously developed [C]UCB-J, a PET radiotracer with high affinity and selectivity toward SV2A; however, the short radioactive half-life (20 min for C) places some limitations on its broader application. Herein, we report the first synthesis of the longer-lived F-labeled counterpart (half-life: 110 min), [F]UCB-J, and its evaluation in nonhuman primates.

Methods: [F]UCB-J was synthesized from the iodonium precursors. PET imaging experiments with [F]UCB-J were conducted in rhesus monkeys to assess the pharmacokinetic and in vivo binding properties. Arterial samples were taken for analysis of radioactive metabolites and generation of input functions. Regional time-activity curves were analyzed using the one-tissue compartment model to derive regional distribution volumes and binding potentials for comparison with [C]UCB-J.

Results: [F]UCB-J was prepared in high radiochemical and enantiomeric purity, but low radiochemical yield. Evaluation in nonhuman primates indicated that the radiotracer displayed pharmacokinetic and imaging characteristics similar to those of [C]UCB-J, with moderate metabolism rate, high brain uptake, fast and reversible binding kinetics, and high specific binding signals.

Conclusion: We have accomplished the first synthesis of the novel SV2A radiotracer [F]UCB-J. [F]UCB-J is demonstrated to be an excellent imaging agent and may prove to be useful for imaging and quantification of SV2A expression, and synaptic density, in humans.
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http://dx.doi.org/10.1007/s00259-019-04357-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6810698PMC
August 2019

Imaging histamine H3 receptors with [ F]FMH3: Test-retest and occupancy studies in the non-human primate.

Synapse 2019 07 23;73(7):e22096. Epub 2019 Mar 23.

XingImaging, LLC, New Haven, Connecticut.

A positron emission tomography (PET) radioligand, [ F]FMH3, has been developed to interrogate histamine receptor subtype 3 (H3R), where dysfunction at this site is linked with obesity, sleep abnormality, and cognitive disorders. [ F]FMH3 was evaluated for imaging central H3R sites in non-human primates through test-retest (TRT) and dose-receptor occupancy studies with two selective H3R antagonists in order to support clinical investigations. Two adult female baboons underwent [ F]FMH3 PET brain scans in the HR+, at repeated baseline (n = 7) and following administration of escalating doses of ABT-239 (0.003-0.1m/kg, n = 4) and ciproxifan (0.5-2.1 mg/kg, n = 7). Volume of distribution (V ) in brain regions was estimated using the 2-tissue compartment model. TRT variability of V across repeated baseline scans was reported as % coefficient of variation (COV). ABT-239 and ciproxifan occupancy at H3R was estimated using the occupancy plot, and the relationship of occupancy with dose and plasma levels was determined. In baboons, distribution of [ F]FMH3 was high in the striatum, intermediate in cortical regions, and low in the brain stem. COV of baseline V was 7.0 ± 3.5%, averaged across regions and animals. Dose-dependent effects of ABT-239 and ciproxifan measured the brain. ED50 and EC50, respectively, were 0.011 mg/kg and 0.942 ng/ml for ABT-239 and 0.73 mg/kg and 208.3 ng/ml for ciproxifan. [ F]FMH3 demonstrated high TRT reliability and can be used to measure occupancy of H3R-targeted drugs. Validation in non-human primates support [ F]FMH3 PET studies toward clinical investigations of H3R.
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http://dx.doi.org/10.1002/syn.22096DOI Listing
July 2019

Evaluation of C-LSN3172176 as a Novel PET Tracer for Imaging M Muscarinic Acetylcholine Receptors in Nonhuman Primates.

J Nucl Med 2019 08 7;60(8):1147-1153. Epub 2019 Feb 7.

Yale PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT; and.

The M muscarinic acetylcholine receptor (mAChR) plays an important role in learning and memory, and therefore is a target for development of drugs for treatment of cognitive impairments in Alzheimer disease and schizophrenia. The availability of M-selective radiotracers for PET will help in developing therapeutic agents by providing an imaging tool for assessment of drug dose-receptor occupancy relationship. Here we report the synthesis and evaluation of C-LSN3172176 (ethyl 4-(6-(methyl- )-2-oxoindolin-1-yl)-[1,4'-bipiperidine]-1'-carboxylate) in nonhuman primates. C-LSN3172176 was radiolabeled via the Suzuki-Miyaura cross-coupling method. PET scans in rhesus macaques were acquired for 2 h with arterial blood sampling and metabolite analysis to measure the input function. Blocking scans with scopolamine (50 μg/kg) and the M-selective agent AZD6088 (0.67 and 2 mg/kg) were obtained to assess tracer binding specificity and selectivity. Regional brain time-activity curves were analyzed with the 1-tissue-compartment model and the multilinear analysis method (MA1) to calculate regional distribution volume. Nondisplaceable binding potential values were calculated using the cerebellum as a reference region. C-LSN3172176 was synthesized with greater than 99% radiochemical purity and high molar activity. In rhesus monkeys, C-LSN3172176 metabolized rapidly (29% ± 6% parent remaining at 15 min) and displayed fast kinetics and extremely high uptake in the brain. Imaging data were modeled well with the 1-tissue-compartment model and MA1 methods. MA1-derived distribution volume values were high (range, 10-81 mL/cm) in all known M mAChR-rich brain regions. Pretreatment with scopolamine and AZD6088 significantly reduced the brain uptake of C-LSN3172176, thus demonstrating its binding specificity and selectivity in vivo. The cerebellum appeared to be a suitable reference region for derivation of nondisplaceable binding potential, which ranged from 2.42 in the globus pallidus to 8.48 in the nucleus accumbens. C-LSN3172176 exhibits excellent in vivo binding and imaging characteristics in nonhuman primates and appears to be the first appropriate radiotracer for PET imaging of human M AChR.
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http://dx.doi.org/10.2967/jnumed.118.222034DOI Listing
August 2019

A Novel F-Labeled Radioligand for Positron Emission Tomography Imaging of 11β-Hydroxysteroid Dehydrogenase (11β-HSD1): Synthesis and Preliminary Evaluation in Nonhuman Primates.

ACS Chem Neurosci 2019 05 19;10(5):2450-2458. Epub 2019 Feb 19.

PET Center, Department of Radiology and Biomedical Imaging , Yale University School of Medicine , 801 Howard Ave , New Haven , Connecticut 06520-8048 , United States.

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of cortisone to cortisol and controls a key pathway in the regulation of stress. Studies have implicated 11β-HSD1 in metabolic diseases including type 2 diabetes and obesity, as well as stress-related disorders and neurodegenerative diseases, such as depression and Alzheimer's disease (AD). We have previously developed [C]AS2471907 as a PET radiotracer to image 11β-HSD1 in the brain of nonhuman primates and humans. However, the radiosynthesis of [C]AS2471907 was unreliable and low-yielding. Here, we report the development of the F-labeled version [F]AS2471907, including the synthesis of two iodonium ylide precursors and the optimization of F-radiosynthesis. Preliminary PET experiments, composed of a baseline scan of [F]AS2471907 and a blocking scan with the reversible 11β-HSD1 inhibitor ASP3662 (0.3 mg/kg), was also conducted in a rhesus monkey to verify the pharmacokinetics of [F]AS2471907 and its specific binding in the brain. The iodonium ylide precursors were prepared in a seven-step synthetic route with an optimized overall yield of ∼2%. [F]AS2471907 was synthesized in good radiochemical purity, with the ortho regioisomer of iodonium ylide providing greater radiochemical yield as compared with the para regioisomer. In monkey brain, [F]AS2471907 displayed high uptake and heterogeneous distribution, while administration of the 11β-HSD1 inhibitor ASP3662 significantly reduced radiotracer uptake, thus demonstrating the binding specificity of [F]AS2471907. Given the longer half-life of F-18 and feasibility for central production and distribution, [F]AS2471907 holds great promise to be a valuable PET radiotracer to image 11β-HSD1 in the brain.
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http://dx.doi.org/10.1021/acschemneuro.8b00715DOI Listing
May 2019

Synthesis and in Vivo Evaluation of a Novel PET Radiotracer for Imaging of Synaptic Vesicle Glycoprotein 2A (SV2A) in Nonhuman Primates.

ACS Chem Neurosci 2019 03 16;10(3):1544-1554. Epub 2018 Nov 16.

PET Center, Department of Radiology and Biomedical Imaging , Yale University School of Medicine , New Haven , Connecticut 06520 , United States.

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 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 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 = 0.58 nM). F-SDM-8 was prepared in high molar activity (241.7 MBq/nmol) and radiochemical purity (>98%). In the brain, 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 C-UCB-J, 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, 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.
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http://dx.doi.org/10.1021/acschemneuro.8b00526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6810685PMC
March 2019

Inside information on xenon adsorption in porous organic cages by NMR.

Chem Sci 2017 Aug 14;8(8):5721-5727. Epub 2017 Jun 14.

NMR Research Unit , University of Oulu , P.O.Box 3000 , 90014 Oulu , Finland . Email:

A solid porous molecular crystal formed from an organic cage, CC3, has unprecedented performance for the separation of rare gases. Here, xenon was used as an internal reporter providing extraordinarily versatile information about the gas adsorption phenomena in the cage and window cavities of the material. Xe NMR measurements combined with state-of-the-art quantum chemical calculations allowed the determination of the occupancies of the cavities, binding constants, thermodynamic parameters as well as the exchange rates of Xe between the cavities. Chemical exchange saturation transfer (CEST) experiments revealed a minor window cavity site with a significantly lower exchange rate than other sites. Diffusion measurements showed significantly reduced mobility of xenon with loading. Xe spectra also revealed that the cage cavity sites are preferred at lower loading levels, due to more favourable binding, whereas window sites come to dominate closer to saturation because of their greater prevalence.
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http://dx.doi.org/10.1039/c7sc01990dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621166PMC
August 2017

The Search for a Subtype-Selective PET Imaging Agent for the GABA Receptor Complex: Evaluation of the Radiotracer [C]ADO in Nonhuman Primates.

Mol Imaging 2017 Jan-Dec;16:1536012117731258

1 Yale PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA.

The myriad physiological functions of γ-amino butyric acid (GABA) are mediated by the GABA-benzodiazepine receptor complex comprising of the GABA, GABA, and GABA groups. The various GABA subunits with region-specific distributions in the brain subserve different functional and physiological roles. For example, the sedative and anticonvulsive effects of classical benzodiazepines are attributed to the α subunit, and the α and α subunits mediate the anxiolytic effect. To optimize pharmacotherapies with improved efficacy and devoid of undesirable side effects for the treatment of anxiety disorders, subtype-selective imaging radiotracers are required to assess target engagement at GABA sites and determine the dose-receptor occupancy relationships. The goal of this work was to characterize, in nonhuman primates, the in vivo binding profile of a novel positron emission tomography (PET) radiotracer, [C]ADO, which has been indicated to have functional selectivity for the GABA α/α subunits. High specific activity [C]ADO was administrated to 3 rhesus monkeys, and PET scans of 120-minute duration were performed on the Focus-220 scanner. In the blood, [C]ADO metabolized at a fairly rapid rate, with ∼36% of the parent tracer remaining at 30 minutes postinjection. Uptake levels of [C]ADO in the brain were high (peak standardized uptake value of ∼3.0) and consistent with GABA distribution, with highest activity levels in cortical areas, intermediate levels in cerebellum and thalamus, and lowest uptake in striatal regions and amygdala. Tissue kinetics was fast, with peak uptake in all brain regions within 20 minutes of tracer injection. The one-tissue compartment model provided good fits to regional time-activity curves and reliable measurement of kinetic parameters. The absolute test-retest variability of regional distribution volumes ( V) was low, ranging from 4.5% to 8.7%. Pretreatment with flumazenil (a subtype nonselective ligand, 0.2 mg/kg, intravenous [IV], n = 1), Ro15-4513 (an α-selective ligand, 0.03 mg/kg, IV, n = 2), and zolpidem (an α-selective ligand, 1.7 mg/kg, IV, n = 1) led to blockade of [C]ADO binding by 96.5%, 52.5%, and 76.5%, respectively, indicating the in vivo binding specificity of the radiotracer. Using the nondisplaceable volume of distribution ( V) determined from the blocking studies, specific binding signals, as measured by values of regional binding potential ( BP), ranged from 0.6 to 4.4, which are comparable to those of [C]flumazenil. In conclusion, [C]ADO was demonstrated to be a specific radiotracer for the GABA receptors with several favorable properties: high brain uptake, fast tissue kinetics, and high levels of specific binding in nonhuman primates. However, subtype selectivity in vivo is not obvious for the radiotracer, and thus, the search for subtype-selective GABA radiotracers continues.
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http://dx.doi.org/10.1177/1536012117731258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5912275PMC
July 2018

Evaluation of the Lysophosphatidic Acid Receptor Type 1 Radioligand C-BMT-136088 for Lung Imaging in Rhesus Monkeys.

J Nucl Med 2018 02 1;59(2):327-333. Epub 2017 Sep 1.

Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut.

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 C-BMT-136088 (1-(4'-(3-methyl-4-(((1()-(3-C-methylphenyl)ethoxy)carbonyl)amino)isoxazol-5-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid) in rhesus monkeys to image LPA1 in the lung in vivo with PET. The study consisted of 3 parts: test-retest scans; self-saturation to estimate the tracer's in vivo dissociation constant, nondisplaceable volume of distribution (), and nondisplaceable binding potential (); and dosimetry. In the first 2 parts, the radiotracer was administered using a bolus-plus-infusion protocol, the arterial input function was measured, and the animals underwent 2 scans per day separated by about 4 h. Lung regions of interest were segmented, and the tissue density estimated, from CT images. A fixed blood volume correction was applied. The tracer volume of distribution () was estimated using multilinear analysis 1 (MA1) or equilibrium analysis (EA). C-BMT-136088 baseline was 1.83 ± 0.16 (MA1, = 5) or 2.1 ± 0.55 (EA, = 7) mL of plasma per gram of tissue in the left and right lung regions of interest, with a test-retest variability of -6% (MA1, = 1) or -1% ± 14% (EA, = 2). For the self-saturation study, C-BMT-136088 and were estimated to be 0.9 ± 0.08 mL of plasma per gram of tissue and 1.1 ± 0.14, respectively. The unlabeled drug dose and plasma concentration leading to a 50% reduction of C-BMT-136088 specific binding were 73 ± 30 nmol/kg and 28 ± 12 nM, respectively. The average plasma free fraction was 0.2%; thus, the tracer's in vivo dissociation constant was estimated to be 55 pM. For the dosimetry study, the highest organ dose was in the liver (43.1 ± 4.9 and 68.9 ± 9.4 μSv/MBq in reference human male and female phantoms, respectively), and the effective dose equivalent was 6.9 ± 0.6 and 8.7 ± 0.6 μSv/MBq, respectively. Specific binding of C-BMT-136088 can be reliably measured to quantify LPA1 in the lungs of rhesus monkeys in vivo.
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http://dx.doi.org/10.2967/jnumed.117.195073DOI Listing
February 2018

Fast Neural Style Transfer for Motion Data.

IEEE Comput Graph Appl 2017 ;37(4):42-49

Automating motion style transfer can help save animators time by allowing them to produce a single set of motions, which can then be automatically adapted for use with different characters. The proposed fast, efficient technique for performing neural style transfer of human motion data uses a feed-forward neural network trained on a large motion database. The proposed framework can transform the style of motion thousands of times faster than previous approaches that use optimization.
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http://dx.doi.org/10.1109/MCG.2017.3271464DOI Listing
October 2018

Computationally-Guided Synthetic Control over Pore Size in Isostructural Porous Organic Cages.

ACS Cent Sci 2017 Jul 20;3(7):734-742. Epub 2017 Jun 20.

Department of Chemistry and Materials Innovation Factory, University of Liverpool, Crown Street, Liverpool L69 7ZD, United Kingdom.

The physical properties of 3-D porous solids are defined by their molecular geometry. Hence, precise control of pore size, pore shape, and pore connectivity are needed to tailor them for specific applications. However, for porous molecular crystals, the modification of pore size by adding pore-blocking groups can also affect crystal packing in an unpredictable way. This precludes strategies adopted for isoreticular metal-organic frameworks, where addition of a small group, such as a methyl group, does not affect the basic framework topology. Here, we narrow the pore size of a cage molecule, , in a systematic way by introducing methyl groups into the cage windows. Computational crystal structure prediction was used to anticipate the packing preferences of two homochiral methylated cages, - and -, and to assess the structure-energy landscape of a -/- cocrystal, designed such that both component cages could be directed to pack with a 3-D, interconnected pore structure. The experimental gas sorption properties of these three cage systems agree well with physical properties predicted by computational energy-structure-function maps.
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http://dx.doi.org/10.1021/acscentsci.7b00145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5532722PMC
July 2017

Novel F-Labeled κ-Opioid Receptor Antagonist as PET Radiotracer: Synthesis and In Vivo Evaluation of F-LY2459989 in Nonhuman Primates.

J Nucl Med 2018 01 26;59(1):140-146. Epub 2017 Jul 26.

PET Center, Yale University School of Medicine, New Haven, Connecticut; and.

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 C-labeled PET radiotracers for KOR imaging in humans. Here we report the synthesis and evaluation of F-LY2459989 as the first F-labeled KOR antagonist radiotracer in nonhuman primates and its comparison with C-LY2459989. The novel radioligand F-LY2459989 was synthesized by F displacement of a nitro group or an iodonium ylide. PET scans in rhesus monkeys were obtained on a small-animal scanner to assess the pharmacokinetic and in vivo binding properties of the ligand. Metabolite-corrected arterial activity curves were measured and used as input functions in the analysis of brain time-activity curves and the calculation of binding parameters. With the iodonium ylide precursor, F-LY2459989 was prepared at high radiochemical yield (36% ± 7% [mean ± SD]), radiochemical purity (>99%), and mean molar activity (1,175 GBq/μmol; = 6). In monkeys, F-LY2459989 was metabolized at a moderate rate, with a parent fraction of approximately 35% at 30 min after injection. Fast and reversible kinetics were observed, with a regional peak uptake time of less than 20 min. Pretreatment with the selective KOR antagonist LY2456302 (0.1 mg/kg) decreased the activity level in regions with high levels of binding to that in the cerebellum, thus demonstrating the binding specificity and selectivity of F-LY2459989 in vivo. Regional time-activity curves were well fitted by the multilinear analysis 1 kinetic model to derive reliable estimates of regional distribution volumes. With the cerebellum as the reference region, regional binding potentials were calculated and ranked as follows: cingulate cortex > insula > caudate/putamen > frontal cortex > temporal cortex > thalamus, consistent with the reported KOR distribution in the monkey brain. The evaluation of F-LY2459989 in nonhuman primates demonstrated many attractive imaging properties: fast tissue kinetics, specific and selective binding to the KOR, and high specific binding signals. A side-by-side comparison of F-LY2459989 and C-LY2459989 indicated similar kinetic and binding profiles for the 2 radiotracers. Taken together, the results indicated that F-LY2459989 appears to be an excellent PET radiotracer for the imaging and quantification of the KOR in vivo.
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http://dx.doi.org/10.2967/jnumed.117.195586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750518PMC
January 2018

Microglial depletion and activation: A [C]PBR28 PET study in nonhuman primates.

EJNMMI Res 2017 Dec 24;7(1):59. Epub 2017 Jul 24.

Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, 06520, USA.

Background: The 18-kDa translocator protein (TSPO) is an important target for assessing neuroimmune function in brain with positron-emission tomography (PET) imaging. The goal of this work was to assess two [C]PBR28 imaging paradigms for measuring dynamic microglia changes in Macaca mulatta.

Methods: Dynamic [C]PBR28 PET imaging data with arterial blood sampling were acquired to quantify TSPO levels as [C]PBR28 V . Scans were acquired at three timepoints: baseline, immediately post-drug, and prolonged post-drug.

Results: In one animal, a colony-stimulating factor 1 receptor kinase inhibitor, previously shown to deplete brain microglia, reduced [C]PBR28 V in brain by 46 ± 3% from baseline, which recovered after 12 days to 7 ± 5% from baseline. In a different animal, acute lipopolysaccharide administration, shown to activate brain microglia, increased [C]PBR28 V in brain by 39 ± 9% from baseline, which recovered after 14 days to -11 ± 3% from baseline.

Conclusions: These studies provide preliminary evidence of complementary paradigms to assess microglia dynamics via in vivo TSPO imaging.
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http://dx.doi.org/10.1186/s13550-017-0305-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524658PMC
December 2017

Understanding gas capacity, guest selectivity, and diffusion in porous liquids.

Chem Sci 2017 Apr 31;8(4):2640-2651. Epub 2017 Jan 31.

Department of Chemistry and Materials Innovation Factory , University of Liverpool , Crown Street , Liverpool , L69 7ZD , UK . Email:

Porous liquids are a new class of material that could have applications in areas such as gas separation and homogeneous catalysis. Here we use a combination of measurement techniques, molecular simulations, and control experiments to advance the quantitative understanding of these liquids. In particular, we show that the cage cavities remain unoccupied in the absence of a suitable guest, and that the liquids can adsorb large quantities of gas, with gas occupancy in the cages as high as 72% and 74% for Xe and SF, respectively. Gases can be reversibly loaded and released by using non-chemical triggers such as sonication, suggesting potential for gas separation schemes. Diffusion NMR experiments show that gases are in dynamic equilibrium between a bound and unbound state in the cage cavities, in agreement with recent simulations for related porous liquids. Comparison with gas adsorption in porous organic cage solids suggests that porous liquids have similar gas binding affinities, and that the physical properties of the cage molecule are translated into the liquid state. By contrast, some physical properties are different: for example, solid homochiral porous cages show enantioselectivity for chiral aromatic alcohols, whereas the equivalent homochiral porous liquids do not. This can be attributed to a loss of supramolecular organisation in the isotropic porous liquid.
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http://dx.doi.org/10.1039/c6sc05196kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431659PMC
April 2017

Functional materials discovery using energy-structure-function maps.

Nature 2017 03 22;543(7647):657-664. Epub 2017 Mar 22.

Computational Systems Chemistry, School of Chemistry, University of Southampton, Southampton, UK.

Molecular crystals cannot be designed in the same manner as macroscopic objects, because they do not assemble according to simple, intuitive rules. Their structures result from the balance of many weak interactions, rather than from the strong and predictable bonding patterns found in metal-organic frameworks and covalent organic frameworks. Hence, design strategies that assume a topology or other structural blueprint will often fail. Here we combine computational crystal structure prediction and property prediction to build energy-structure-function maps that describe the possible structures and properties that are available to a candidate molecule. Using these maps, we identify a highly porous solid, which has the lowest density reported for a molecular crystal so far. Both the structure of the crystal and its physical properties, such as methane storage capacity and guest-molecule selectivity, are predicted using the molecular structure as the only input. More generally, energy-structure-function maps could be used to guide the experimental discovery of materials with any target function that can be calculated from predicted crystal structures, such as electronic structure or mechanical properties.
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http://dx.doi.org/10.1038/nature21419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458805PMC
March 2017

PET Imaging Evaluation of Four σ Radiotracers in Nonhuman Primates.

J Nucl Med 2017 06 23;58(6):982-988. Epub 2017 Feb 23.

PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut

The σ receptors (S1Rs) are implicated in a variety of diseases including Alzheimer disease and cancer. Previous PET S1R radiotracers are characterized by slow kinetics or off-target binding that impedes their use in humans. Here, we report the first PET imaging evaluation in rhesus monkeys of 4 F-labeled spirocyclic piperidine-based PET radiotracers (F- to F-). Baseline scans for the 4 radiotracers were obtained on an adult male rhesus monkey. Blocking scans were obtained with the S1R-selective agonist SA4503 to assess binding specificity of F- and F- Arterial input functions were measured, and binding parameters were determined with kinetic modeling analysis. In the rhesus brain, all 4 radiotracers showed high and fast uptake. Tissue activity washout was rapid for F- and F-, and much slower for F- and F-, in line with their respective in vitro S1R-binding affinities. Both the 1-tissue-compartment and multilinear analysis-1 kinetic models provided good fits of time-activity curves and reliable estimates of distribution volume. Regional distribution volume values were highest in the cingulate cortex and lowest in the thalamus for all radiotracers. F- showed greater differential uptake across brain regions and 3-fold-higher binding potential than F- SA4503 at the dose of 0.5 mg/kg blocked approximately 85% (F-) and 95% (F-) of radiotracer binding. Tracers F- and F- displayed high brain uptake and fast tissue kinetics, with F- having higher specific binding signals than F- in the same monkey. Taken together, these data indicate that both F- and F- possess the requisite kinetic and imaging properties as viable PET tracers for imaging S1R in the human brain.
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http://dx.doi.org/10.2967/jnumed.116.188052DOI Listing
June 2017

A multi species evaluation of the radiation dosimetry of [C]erlotinib, the radiolabeled analog of a clinically utilized tyrosine kinase inhibitor.

Nucl Med Biol 2017 Apr 2;47:56-61. Epub 2017 Jan 2.

Department of Biomedical Engineering, Yale University, New Haven, CT, United States; Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, United States. Electronic address:

Introduction: Erlotinib is a tyrosine kinase inhibitor prescribed for non-small cell lung cancer (NSCLC) patients bearing epidermal growth factor receptor mutations in the kinase domain. The objectives of this study were to (1) establish a human dosimetry profile of [C]erlotinib and (2) assess the consistency of calculated equivalent dose across species using the same dosimetry model.

Methods: Subjects examined in this multi-species study included: a stage IIIa NSCLC patient, 3 rhesus macaque monkeys, a landrace pig, and 4 athymic nude-Fox1nu mice. [C]erlotinib PET data of the whole body were acquired dynamically for up to 120min. Regions of interest (ROIs) were manually drawn to extract PET time activity curves (TACs) from identifiable organs. TACs were used to calculate time-integrated activity coefficients (residence times) in each ROI, which were then used to calculate the equivalent dose in OLINDA. Subject data were used to predict the equivalent dose to the organs of a 73.7kg human male.

Results: In three of four species, the liver was identified as the organ receiving the highest equivalent dose (critical organ). The mean equivalent doses per unit of injected activity to the liver based on human, monkey, and mouse data were 29.4μSv/MBq, 17.4±6.0μSv/MBq, and 5.27±0.25μSv/MBq, respectively. The critical organ based on the pig data was the gallbladder wall (20.4μSv/MBq) but the liver received a nearly identical equivalent dose (19.5μSv/MBq).

Conclusions: (1) When designing PET studies using [C]erlotinib, the liver should be considered the critical organ. (2) In organs receiving the greatest equivalent dose, mouse data underestimated the dose in comparison to larger species. However, the effective dose of [C]erlotinib to the whole body of a 73.7kg man was predicted with good consistency based on mice (3.14±0.05μSv/MBq) or the larger species (3.46±0.25μSv/MBq).
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http://dx.doi.org/10.1016/j.nucmedbio.2016.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360653PMC
April 2017

PET imaging of α nicotinic acetylcholine receptors: a comparative study of [F]ASEM and [F]DBT-10 in nonhuman primates, and further evaluation of [F]ASEM in humans.

Eur J Nucl Med Mol Imaging 2017 Jun 24;44(6):1042-1050. Epub 2017 Jan 24.

PET Center, Yale University, PO Box 208048, 801 Howard Ave, New Haven, CT, 06520-8048, USA.

Purpose: The α nicotinic acetylcholine receptor (nAChR) is implicated in many neuropsychiatric disorders, making it an important target for positron emission tomography (PET) imaging. The first aim of this work was to compare two α nAChRs PET radioligands, [F]ASEM (3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-([F]fluorodibenzo[b,d]thiophene 5,5-dioxide) and [F]DBT-10 (7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-([F]fluorodibenzo[b,d]thiophene 5,5-dioxide), in nonhuman primates. The second aim was to assess further the quantification and test-retest variability of [F]ASEM in humans.

Methods: PET scans with high specific activity [F]ASEM or [F]DBT-10 were acquired in three rhesus monkeys (one male, two female), and the kinetic properties of these radiotracers were compared. Additional [F]ASEM PET scans with blocking doses of nicotine, varenicline, and cold ASEM were acquired separately in two animals. Next, six human subjects (five male, one female) were imaged with [F]ASEM PET for 180 min, and arterial sampling was used to measure the parent input function. Different modeling approaches were compared to identify the optimal analysis method and scan duration for quantification of [F]ASEM distribution volume (V ). In addition, retest scans were acquired in four subjects (three male, one female), and the test-retest variability of V was assessed.

Results: In the rhesus monkey brain [F]ASEM and [F]DBT-10 exhibited highly similar kinetic profiles. Dose-dependent blockade of [F]ASEM binding was observed, while administration of either nicotine or varenicline did not change [F]ASEM V . [F]ASEM was selected for further validation because it has been used in humans. Accurate quantification of [F]ASEM V in humans was achieved using multilinear analysis with at least 90 min of data acquisition, resulting in V values ranging from 19.6 ± 2.5 mL/cm in cerebellum to 25.9 ± 2.9 mL/cm in thalamus. Test-retest variability of V was 11.7 ± 9.8%.

Conclusions: These results confirm [F]ASEM as a suitable radiotracer for the imaging and quantification of α nAChRs in humans.
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http://dx.doi.org/10.1007/s00259-017-3621-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400702PMC
June 2017

Learning Inverse Rig Mappings by Nonlinear Regression.

IEEE Trans Vis Comput Graph 2017 03 11;23(3):1167-1178. Epub 2016 Nov 11.

We present a framework to design inverse rig-functions-functions that map low level representations of a character's pose such as joint positions or surface geometry to the representation used by animators called the animation rig. Animators design scenes using an animation rig, a framework widely adopted in animation production which allows animators to design character poses and geometry via intuitive parameters and interfaces. Yet most state-of-the-art computer animation techniques control characters through raw, low level representations such as joint angles, joint positions, or vertex coordinates. This difference often stops the adoption of state-of-the-art techniques in animation production. Our framework solves this issue by learning a mapping between the low level representations of the pose and the animation rig. We use nonlinear regression techniques, learning from example animation sequences designed by the animators. When new motions are provided in the skeleton space, the learned mapping is used to estimate the rig controls that reproduce such a motion. We introduce two nonlinear functions for producing such a mapping: Gaussian process regression and feedforward neural networks. The appropriate solution depends on the nature of the rig and the amount of data available for training. We show our framework applied to various examples including articulated biped characters, quadruped characters, facial animation rigs, and deformable characters. With our system, animators have the freedom to apply any motion synthesis algorithm to arbitrary rigging and animation pipelines for immediate editing. This greatly improves the productivity of 3D animation, while retaining the flexibility and creativity of artistic input.
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http://dx.doi.org/10.1109/TVCG.2016.2628036DOI Listing
March 2017
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