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Dopamine Receptor Studies with Positron Emission Tomography
Published in W. R. Wayne Martin, Functional Imaging in Movement Disorders, 2019
Lindvall et al.58 used 11C-raclopride and an equilibrium PET method to investigate receptor binding in two parkinsonian patients taking levodopa before and after transplantation of adrenal medullary grafts to the right putamen. The surgery was performed in the hope that the grafted tissue would produce dopamine in situ. The striatal-to-cerebellar ratios before and after surgery were not different from controls. In one subject (the 63 year old), a small dose (about 10 μg) of unlabeled raclopride was injected with 11C-raclopride followed by a study using a saturating dose of unlabeled raclopride (about 200μg). No comment was made about the clinical effect from this dose of raclopride. In this patient, Bmax was calculated using the equilibrium method discussed above and found to be reduced compared to values from younger, healthy controls. Bmax was essentially unchanged after surgery. It would be interesting to know whether this difference existed in comparison to age-matched controls.
Imaging Dopamine Signaling in Addiction
Published in Hanna Pickard, Serge H. Ahmed, The Routledge Handbook of Philosophy and Science of Addiction, 2019
Diana Martinez, Felipe Castillo
In addition to measuring receptors, PET can also be used to image changes in neurotransmitter levels in the brain. The PET radiotracer most frequently used to image dopamine is [11C]raclopride, which binds to the D2 family of receptors (referred to as D2 for simplicity). In addition to measuring D2 receptor levels, [11C]raclopride can be used to measure changes in extracellular dopamine in specific regions in the brain. This is shown in the top panel of Figure 30.2, where the highest uptake of [11C]raclopride is seen in the striatum, which contains the caudate, putamen, and nucleus accumbens. The striatum has the highest density of D2 receptors in the brain, and dopamine is released in high levels in this brain region.
Neurodysfunction in Addiction and Overeating as Assessed by Brain Imaging
Published in Joan Ifland, Marianne T. Marcus, Harry G. Preuss, Processed Food Addiction: Foundations, Assessment, and Recovery, 2017
Randall J. Ellis, Michael Michaelides, Gene-Jack Wang
Dopamine release can be assessed in humans indirectly using [11C]raclopride as a PET tracer. Volkow et al. were the first to show that methylphenidate and cocaine compete for the same dopamine binding sites (1995). Both cocaine and methylphenidate bind to and inhibit the dopamine transporter (DAT). DAT is the protein responsible for recycling dopamine from the synapse back into the cytosol of a presynaptic neuron, a process known as reuptake (Volkow et al., 2002). By inhibiting the action of DAT, synaptic dopamine is increased and this is thought to underlie in part the reinforcing and rewarding aspects of cocaine and other dopaminergic drugs. Dopamine displaces [11C]raclopride at dopamine D2 receptors, and by assessing the binding of [11C]raclopride to dopamine D2 receptors with PET before administering methylphenidate to these subjects, it can be deduced how much dopamine has been released. That is, if large quantities of dopamine are released in the brain, [11C]raclopride will show low binding from being displaced at dopamine receptors. If dopamine levels decline, [11C]raclopride will show high binding because of the greater availability of binding sites.
What is the role of placebo in neurotherapeutics?
Published in Expert Review of Neurotherapeutics, 2022
Elisa Frisaldi, Aziz Shaibani, Marco Trucco, Edoardo Milano, Fabrizio Benedetti
In the case of patients affected by PD, the placebo procedure consists in administering an inert substance (placebo) along with the information that it is an anti-parkinsonian drug that produces an improvement in motor performance. In 2001, the first brain imaging study of the placebo effect by means of PET was conducted [46]. In this study, patients were aware that they would be receiving an injection of either active drug (apomorphine, a dopamine receptor agonist) or placebo (an inert substance that the patient believed to be apomorphine), according to classic clinical trials methodology. The authors assessed the competition between endogenous dopamine and [11C]-raclopride for D2/D3 receptors, a method that allows identification of endogenous dopamine release. After placebo administration, a release of dopamine was found in the striatum (both dorsal and ventral), corresponding to a change of 200% or more in extracellular dopamine concentration. However, while dopamine release in dorsal striatum was greater in those patients who reported clinical improvement, its release in the ventral striatum (nucleus accumbens) was associated with patient expectation of improvement in symptoms [46,47].
Advanced clinical imaging for the evaluation of stem cell based therapies
Published in Expert Opinion on Biological Therapy, 2021
Michail E. Klontzas, George A. Kakkos, Georgios Z. Papadakis, Kostas Marias, Apostolos H. Karantanas
Apart from fluorine-18, other PET-emitters have gained interest for PET-based molecular imaging of stem cells either for clinical or pre-clinical purposes. In the pre-clinical setting, 11 C-raclopride, a selective dopamine D2/D3 antagonist radio-labeled with carbon-11 (11 C; physical half-life of 20.364 mins), has been used to monitor functional recovery of brains after the injection of iron oxide labeled BMMSCs in the striatum of hemi-parkinsonian rats [85]. Asiedu et al. visualized and quantified the recruitment of BMMSCs in bone fractures with the use of zirconium-89 (89Zr; PET-emitter with physical half-life of 78.41 hours) – oxine-labeled BMMSCs [86]. 19Cu-NODAGA-RGD has been used to target integrins in endothelial cells indicating angiogenesis after dental pulp stem cell treatment of critical bone defects. In their study, Collignon et al. combined 19Cu-NODAGA-RGD with 18 F-Na PET to show angiogenesis combined with calcium deposition in bone defects [87].
Pharmacokinetics and metabolism of brexpiprazole, a novel serotonin-dopamine activity modulator and its main metabolite in rat, monkey and human
Published in Xenobiotica, 2021
Hiroyuki Sasabe, Toshihisa Koga, Masayuki Furukawa, Masayuki Matsunaga, Yosuke Kaneko, Noriyuki Koyama, Yukihiro Hirao, Hitomi Akazawa, Mitsuhiko Kawabata, Eiji Kashiyama, Kenji Takeuchi
Brexpiprazole (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butyloxy}quinolin-2(1H)-one, Figure 1) and its metabolites, DM-3411, were synthesised by Otsuka Pharmaceutical Co., Ltd (Tokyo, Japan). [quinoline ring-4-14C]Brexpiprazole (abbreviated as q-[14C]brexpiprazole) and [benzothiophene-3-14C]brexpiprazole (b-[14C]brexpiprazole) were synthesised by Daiichi Pure Chemicals Co., Ltd (Tokyo, Japan). Specific radioactivity was 5.07 MBq/mg and 4.92 MBq/mg, respectively. [3H]Raclopride, a substrate for D2 receptors was supplied by (PerkinElmer Inc., Waltham, MA). β-Nicotinamide adenine dinucleotide, reduced form (β-NADPH) and β-nicotinamide adenine dinucleotide phosphate, reduced form (β-NADH), and all CYP inhibitors were purchased from Sigma-Aldrich Co. (St. Louis, MO). All reagents and solvents were of analytical or HPLC grade, the highest grade or equivalent.