18F-MCL-524, an 18F-Labeled Dopamine D2 and D3 Receptor Agonist Sensitive to Dopamine: A Preliminary PET Study
| Autor: | Vladimir Stepanov, Cathrine Jonsson, Lars Farde, Michael G. Stabin, Christer Halldin, Sjoerd J. Finnema, Tangzhi Zhang, Philip Seeman, Anna W. Sromek, Ryuji Nakao, John L. Neumeyer, Susan R. George |
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| Rok vydání: | 2014 |
| Předmět: |
Agonist
Apomorphine medicine.drug_class Dopamine Pharmacology Medicinal chemistry Article chemistry.chemical_compound Column chromatography Dopamine receptor D3 Dopamine receptor D2 medicine Trifluoroacetic acid Animals Radiology Nuclear Medicine and imaging Radiometry Radiochemistry Receptors Dopamine D2 Chemistry Receptors Dopamine D3 Thin-layer chromatography Solvent Kinetics Macaca fascicularis Isotope Labeling Positron-Emission Tomography Yield (chemistry) |
| Zdroj: | Journal of Nuclear Medicine. 55:1164-1170 |
| ISSN: | 2159-662X 0161-5505 |
| Popis: | PET has been used to examine changes in neurotransmitter concentrations in the living brain. Pioneering PET studies on the dopamine system have used D2 and D3 receptor (D2/D3) antagonists such as (11)C-raclopride. However, more recently developed agonist radioligands have shown enhanced sensitivity to endogenous dopamine. A limitation of available agonist radioligands is that they incorporate the short-lived radioisotope (11)C. In the current study, we developed the (18)F-labeled D2/D3 receptor agonist (R)-(-)-2-(18)F-fluoroethoxy-N-n-propylnorapomorphine ((18)F-MCL-524).In total, 10 PET measurements were conducted on 5 cynomolgus monkeys. Initially, the binding of (18)F-MCL-524 was compared with that of (11)C-MNPA in 3 monkeys. Second, the specificity of (18)F-MCL-524 binding was examined in pretreatment studies using raclopride (1.0 mg/kg) and d-amphetamine (1.0 mg/kg). Third, a preliminary kinetic analysis was performed using the radiometabolite-corrected arterial input function of the baseline studies. Finally, 2 whole-body PET measurements were conducted to evaluate biodistribution and radiation dosimetry after intravenous injection of (18)F-MCL-524.(18)F-MCL-524 entered the brain and provided striatum-to-cerebellum ratios suitable for reliable quantification of receptor binding using the multilinear reference tissue model. Mean striatal nondisplaceable binding potential (BPND) values were 2.0 after injection of (18)F-MCL-524 and 1.4 after (11)C-MNPA. The ratio of the BPND values of (18)F-MCL-524 and (11)C-MNPA was 1.5 across striatal subregions. After administration of raclopride and d-amphetamine, the (18)F-MCL-524 BPND values were reduced by 89% and 56%, respectively. Preliminary kinetic analysis demonstrated that BPND values obtained with the 1-tissue- and 2-tissue-compartment models were similar to values obtained with the multilinear reference tissue model. Estimated radiation doses were highest for gallbladder (0.27 mSv/MBq), upper large intestine (0.19 mSv/MBq), and small intestine (0.17 mSv/MBq). The estimated effective dose was 0.035 mSv/MBq.The (18)F-labeled agonist (18)F-MCL-524 appears suitable for quantification of D2/D3 receptor binding in vivo, and the results encourage extension to human studies. The longer half-life of (18)F makes (18)F-MCL-524 attractive for studies on modulation of the dopamine concentration-for example, in combination with simultaneous measurement of changes in blood-oxygen-level-dependent signal using bimodal PET/functional MRI. |
| Databáze: | OpenAIRE |
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