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Adam J Stark, Christopher T Smith, Kalen J Petersen, Paula Trujillo, Nelleke C van Wouwe, Manus J Donahue, Robert M Kessler, Ariel Y Deutch, David H Zald, Daniel O Claassen
Parkinson's disease (PD) is characterized by widespread degeneration of monoaminergic (especially dopaminergic) networks, manifesting with a number of both motor and non-motor symptoms. Regional alterations to dopamine D2/3 receptors in PD patients are documented in striatal and some extrastriatal areas, and medications that target D2/3 receptors can improve motor and non-motor symptoms. However, data regarding the combined pattern of D2/3 receptor binding in both striatal and extrastriatal regions in PD are limited...
2018: NeuroImage: Clinical
Deana Haralampieva, Souzan Salemi, Thomas Betzel, Ivana Dinulovic, Stefanie D Krämer, Roger Schibli, Tullio Sulser, Christoph Handschin, Simon M Ametamey, Daniel Eberli
While many groups demonstrated new muscle tissue formation after muscle precursor cell (MPC) injection, the capacity of these cells to heal muscle damage, for example, sphincter in stress urinary incontinence, in long-term is still limited. Therefore, the first goal of our project was to optimize the functional regenerative potential of hMPC by genetic modification to overexpress human peroxisome proliferator-activated receptor gamma coactivator 1-alpha (hPGC-1 α ), key regulator of exercise-mediated adaptation...
2018: Stem Cells International
Ren Iwata, Claudio Pascali, Kazunori Terasaki, Yoichi Ishikawa, Shozo Furumoto, Kazuhiko Yanai
High specific activity is often a significant requirement for radiopharmaceuticals. To achieve that with18 F-labeled probes, it is mandatory to start from no-carrier-added fluoride and to reduce to a minimum the amount of precursor in order to decrease the presence of any pseudo-carrier. In the present study a feasible and efficient method for microscale one-pot radiosynthesis of18 F-labeled probes is described. It allows a substantial reduction in precursor, solvent and reagents, thus reducing also possible side reaction in the case of base-sensitive precursors...
March 8, 2018: Journal of Labelled Compounds & Radiopharmaceuticals
Teresa Mann, Jens Kurth, Alexander Hawlitschka, Jan Stenzel, Tobias Lindner, Stefan Polei, Alexander Hohn, Bernd J Krause, Andreas Wree
Intrastriatal injection of botulinum neurotoxin A (BoNT-A) results in improved motor behavior of hemiparkinsonian (hemi-PD) rats, an animal model for Parkinson's disease. The caudate-putamen (CPu), as the main input nucleus of the basal ganglia loop, is fundamentally involved in motor function and directly interacts with the dopaminergic system. To determine receptor-mediated explanations for the BoNT-A effect, we analyzed the dopamine D₂/D₃ receptor (D₂/D₃R) in the CPu of 6-hydroxydopamine (6-OHDA)-induced hemi-PD rats by [18 F]fallypride-PET/CT scans one, three, and six months post-BoNT-A or -sham-BoNT-A injection...
March 6, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Adam J Stark, Christopher T Smith, Ya-Chen Lin, Kalen J Petersen, Paula Trujillo, Nelleke C van Wouwe, Hakmook Kang, Manus J Donahue, Robert M Kessler, David H Zald, Daniel O Claassen
The nigrostriatal and mesocorticolimbic dopamine networks regulate reward-driven behavior. Regional alterations to mesolimbic dopamine D2/3 receptor expression are described in drug-seeking and addiction disorders. Parkinson's disease (PD) patients are frequently prescribed D2 -like dopamine agonist (DAgonist) therapy for motor symptoms, yet a proportion develop clinically significant behavioral addictions characterized by impulsive and compulsive behaviors (ICBs). Until now, changes in D2/3 receptor binding in both striatal and extrastriatal regions have not been concurrently quantified in this population...
February 24, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Xiang Zhang, Ryan Dunlow, Burchelle N Blackman, Rolf E Swenson
Traditional radiosynthetic optimization faces the challenges of high radiation exposure, cost and inability to perform serial reactions due to tracer decay. To accelerate tracer development, we have developed a strategy to simulate radioactive 18 F-syntheses by using tracer-level (nanomolar) non-radioactive 19 F-reagents and LC-MS/MS analysis. The methodology was validated with fallypride synthesis under tracer-level 19 F-conditions, which showed reproducible and comparable results with radiosynthesis, and proved the feasibility of this process...
January 16, 2018: Journal of Labelled Compounds & Radiopharmaceuticals
Chenrong Huang, Ziteng Wang, Linsheng Liu, Xiaoxue Liu, Ji Dong, Qingqing Xu, Bin Zhang, Liyan Miao
The purpose of this study was to measure dopamine D2/3 receptor occupancy (RO) as a marker of the clinical efficacy of ropinirole in rats via positron emission tomography (PET) using 18F-fallypride as the radiotracer and to explore the relationship between dopamine RO and the plasma concentration of ropinirole via pharmacokinetic-pharmacodynamic modeling. Plasma was collected from 16 rats treated with one of four doses of ropinirole. For the time-dependent study, the data of 16 rats in the 15 mg/kg dose group at four time points were averaged, and another 24 rats were divided into three dose groups (5 mg/kg, 30 mg/kg and 60 mg/kg) for the dose-dependent study; the animals were assessed via 18F-fallypride PET scans...
January 15, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Lauri Nummenmaa, Lauri Tuominen, Jussi Hirvonen
Positron emission tomography (PET) and endogenous competition paradigms are widely used for studying neuroreceptor activation in humans in vivo. Changes in cerebral blood triggered by the experimentation, such as amphetamine administration, could influence both tracer delivery and washout, thus biasing the results. A recent study tested this assumption in baboons by measuring radiotracer binding with PET while measuring simultaneously cerebral blood flow with arterial spin labeled functional magnetic resonance imaging...
January 5, 2018: ACS Chemical Neuroscience
Linh C Dang, Gregory R Samanez-Larkin, Christopher T Smith, Jaime J Castrellon, Scott F Perkins, Ronald L Cowan, Daniel O Claassen, David H Zald
The fat mass and obesity associated gene (FTO) was the first gene identified by genome-wide association studies to correlate with higher body mass index (BMI) and increased odds of obesity. FTO remains the locus with the largest and most replicated effect on body weight, but the mechanism whereby FTO affects body weight and the development of obesity is not fully understood. Here we tested whether FTO is associated with differences in food cravings and a key aspect of dopamine function that has been hypothesized to influence food reward mechanisms...
December 9, 2017: Physiology & Behavior
Zuzana Kasanova, Jenny Ceccarini, Michael J Frank, Thérèse van Amelsvoort, Jan Booij, Esther van Duin, Henrietta Steinhart, Thomas Vaessen, Alexander Heinzel, Felix Mottaghy, Inez Myin-Germeys
BACKGROUND: Abnormalities in reward learning in psychotic disorders have been proposed to be linked to dysregulated subcortical dopaminergic (DA) neurotransmission, which in turn is a suspected mechanism for predisposition to psychosis. We therefore explored the striatal dopaminergic modulation of reward processing and its behavioral correlates in individuals at familial risk for psychosis. METHODS: We performed a DA D2/3 receptor [18F]fallypride positron emission tomography scan during a probabilistic reinforcement learning task in 16 healthy first-degree relatives of patients with psychosis and 16 healthy volunteers, followed by a 6-day ecological momentary assessment study capturing reward-oriented behavior in the everyday life...
December 13, 2017: Psychological Medicine
Jia Wang, Philip H Chao, Sebastian Hanet, R Michael van Dam
Despite the increasing importance of positron emission tomography (PET) imaging in research and clinical management of disease, access to myriad new radioactive tracers is severely limited due to their short half-lives (which requires daily production) and the high cost and complexity of tracer production. The application of droplet microfluidics based on electrowetting-on-dielectric (EWOD) to the field of radiochemistry can significantly reduce the amount of radiation shielding necessary for safety and the amount of precursor and other reagents needed for the synthesis...
December 5, 2017: Lab on a Chip
Christopher T Smith, Jennifer L Crawford, Linh C Dang, Kendra L Seaman, M Danica San Juan, Aishwarya Vijay, Daniel T Katz, David Matuskey, Ronald L Cowan, Evan D Morris, David H Zald, Gregory R Samanez-Larkin
The relatively modest spatial resolution of positron emission tomography (PET) increases the likelihood of partial volume effects such that binding potential (BPND) may be underestimated. Given structural grey matter losses across adulthood, partial volume effects may be even more problematic in older age leading to overestimation of adult age differences. Here we examined the effects of partial volume correction (PVC) in two studies from different sites using different high-affinity D2-like radioligands (18 F-Fallypride, 11C-FLB457) and different PET camera resolutions (∼5 mm, 2...
January 1, 2017: Journal of Cerebral Blood Flow and Metabolism
Heather Liu, Yasmin Zakiniaeiz, Kelly P Cosgrove, Evan D Morris
The mesocorticolimbic dopamine (DA) circuit, comprising the mesolimbic and mesocortical DA pathways, plays a crucial role in reward, cognitive control, and motivation. The positron emission tomography (PET) radiotracer, [C-11]raclopride, has been used widely to image DA receptors and DA changes in the mesolimbic pathway before and after pharmacological and behavioral challenges. In certain circumstances, properties of traditional kinetic models-used to analyze dynamic PET data-are not well-suited to describing the effects of stimulus-induced DA release...
October 25, 2017: Brain Imaging and Behavior
Sanhita Sinharay, Dianne Lee, Swati Shah, Siva Muthusamy, Georgios Z Papadakis, Xiang Zhang, Dragan Maric, William C Reid, Dima A Hammoud
INTRODUCTION: In vivo imaging biomarkers of various HIV neuropathologies, including dopaminergic dysfunction, are still lacking. Towards developing dopaminergic biomarkers of brain involvement in HIV, we assessed the pre and postsynaptic components of the dopaminergic system in the HIV-1 transgenic rat (Tg), a well-characterized model of treated HIV+ patients, using small-animal PET imaging. METHODS: Fifteen to 18 month-old Tg and wild type (WT) rats were imaged with both [18F]-FP-CMT, a dopamine transporter (DAT) ligand (n=16), and [18F]-Fallypride, a D2/D3 dopamine receptor (D2/D3DR) ligand (n=16)...
December 2017: Nuclear Medicine and Biology
Julia P Dunn, Naji N Abumrad, Robert M Kessler, Bruce W Patterson, Rui Li, Pamela Marks-Shulman, Robyn A Tamboli
OBJECTIVE: It has been previously reported that early after Roux-en-Y-gastric bypass, dopamine (DA) type 2 and 3 receptor (D2/3R) binding potential (BPND ) was decreased from preoperative levels. The current study aimed to determine whether calorie restriction without weight loss modifies D2/3R BPND and whether such changes are explained by neuroendocrine regulation. METHODS: Fifteen females with obesity (BMI = 39 ± 6 kg/m2 ) were studied before and after ∼10 days of a very-low-calorie-diet (VLCD)...
November 2017: Obesity
Linh C Dang, Gregory R Samanez-Larkin, Jaime J Castrellon, Scott F Perkins, Ronald L Cowan, Paul A Newhouse, David H Zald
Spontaneous eye blink rate (EBR) has been proposed as a noninvasive, inexpensive marker of dopamine functioning. Support for a relation between EBR and dopamine function comes from observations that EBR is altered in populations with dopamine dysfunction and EBR changes under a dopaminergic manipulation. However, the evidence across the literature is inconsistent and incomplete. A direct correlation between EBR and dopamine function has so far been observed only in nonhuman animals. Given significant interest in using EBR as a proxy for dopamine function, this study aimed to verify a direct association in healthy, human adults...
September 2017: ENeuro
Gil Leurquin-Sterk, Jenny Ceccarini, Cleo Lina Crunelle, Akila Weerasekera, Bart de Laat, Uwe Himmelreich, Guy Bormans, Koen Van Laere
Converging preclinical evidence links extrastriatal dopamine release and glutamatergic transmission via the metabotropic glutamate receptor 5 (mGluR5) to the rewarding properties of alcohol. To date, human evidence is lacking on how and where in the brain these processes occur. Mesocorticolimbic dopamine release upon intravenous alcohol administration and mGluR5 availability were measured in 11 moderate social drinkers by single-session [(18) F]fallypride and [(18) F]FPEB positron emission tomography, respectively...
September 8, 2017: Addiction Biology
Suzanne Reeves, Julie Bertrand, Emma McLachlan, Fabrizia D'Antonio, Stuart Brownings, Akshay Nair, Suki Greaves, Alan Smith, Joel T Dunn, Paul Marsden, Robert Kessler, Hiroyuki Uchida, David Taylor, Robert Howard
OBJECTIVE: We have previously reported high dopamine D2/3 receptor occupancies at low amisulpride concentrations in older people with Alzheimer's disease (AD), during off-label treatment of AD-related psychosis. This post hoc analysis explored pharmacokinetic (concentration) and pharmacodynamic (prolactin, D2/3 occupancy) contributions to symptom reduction and extrapyramidal side effects (EPS) to inform AD-specific dose adjustments. METHODS: Population pharmacokinetic-pharmacodynamic models were developed by combining pharmacokinetic data from a phase 1 study in 20 healthy older people with pharmacokinetic prolactin, [¹⁸F]fallypride D2/3 receptor imaging, and clinical outcome data from 28 older patients prescribed open amisulpride (25-75 mg/d) to treat AD-related psychosis...
July 2017: Journal of Clinical Psychiatry
Robert H Mach, Robert R Luedtke
The dopamine D2-like receptors (i.e., D2/3 receptors) have been the most extensively studied CNS receptor with PET. The three different radiotracers which have been used in these studies are [(11) C]raclopride, [(18) F]fallypride, and [(11) C]PHNO. Since these radiotracers have a high affinity for both dopamine D2 and D3 receptors, the density of dopamine receptors in the CNS is reported as the D2/3 binding potential, which reflects a measure of the density of both receptor subtypes. Although the development of D2- and D3-selective PET radiotracers has been an active area of research for many years, this by and large presents an unmet need in the area of translational PET imaging studies...
August 31, 2017: Journal of Labelled Compounds & Radiopharmaceuticals
Jennifer E Naylor, Takato Hiranita, Katelin S Matazel, Xuan Zhang, Merle G Paule, Amy K Goodwin
BACKGROUND: Nicotine, the principal psychoactive tobacco constituent, is thought to produce its reinforcing effects via actions within the mesolimbic dopamine (DA) system. The objective of the current study was to examine the effect of nicotine on DA D2/D3 receptor availability in the nonhuman primate brain with the use of the radioligand [(18)F]fallypride and positron emission tomography (PET). METHODS: Ten adult male squirrel monkeys were used in the current study...
August 8, 2017: Drug and Alcohol Dependence
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