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- Chiotis, Konstantinos, et al.
(författare)
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Dual tracer tau PET imaging reveals different molecular targets for C-11-THK5351 and C-11-PBB3 in the Alzheimer brain
- 2018
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 45:9, s. 1605-1617
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Tidskriftsartikel (refereegranskat)abstract
- Several tau PET tracers have been developed, but it remains unclear whether they bind to the same molecular target on the heterogeneous tau pathology. In this study we evaluated the binding of two chemically different tau-specific PET tracers (C-11-THK5351 and C-11-PBB3) in a head-to-head, in vivo, multimodal design. Nine patients with a diagnosis of mild cognitive impairment or probable Alzheimer's disease and cerebrospinal fluid biomarker evidence supportive of the presence of Alzheimer's disease brain pathology were recruited after thorough clinical assessment. All patients underwent imaging with the tau-specific PET tracers C-11-THK5351 and C-11-PBB3 on the same day, as well as imaging with the amyloid-beta-specific tracer C-11-AZD2184, a T1-MRI sequence, and neuropsychological assessment. The load and regional distribution of binding differed between C-11-THK5351 and C-11-PBB3 with no statistically significant regional correlations observed between the tracers. The binding pattern of C-11-PBB3, but not that of C-11-THK5351, in the temporal lobe resembled that of C-11-AZD2184, with strong correlations detected between C-11-PBB3 and C-11-AZD2184 in the temporal and occipital lobes. Global cognition correlated more closely with C-11-THK5351 than with C-11-PBB3 binding. Similarly, cerebrospinal fluid tau measures and entorhinal cortex thickness were more closely correlated with C-11-THK5351 than with C-11-PBB3 binding. This research suggests different molecular targets for these tracers; while C-11-PBB3 appeared to preferentially bind to tau deposits with a close spatial relationship to amyloid-beta, the binding pattern of C-11-THK5351 fitted the expected distribution of tau pathology in Alzheimer's disease better and was more closely related to downstream disease markers.
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| 2. |
- Rahman, Obaidur, et al.
(författare)
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Synthesis of ([C-11]carbonyl)raclopride and a comparison with ([C-11]methyl)raclopride in a monkey PET study
- 2015
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Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 42:11, s. 893-898
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The selective dopamine D-2 receptor antagonist raclopride is usually labeled with carbon-11 using [C-11]methyl iodide or [C-11]methyl triflate for use in the quantification of dopamine D-2 receptors in human brain. The aim of this work was to label raclopride at the carbonyl position using [C-11]carbon monoxide chemistry and to compare ([C-11]carbonyl)raclopride with ([C-11]methyl)raclopride in non-human primate (NHP) using PET with regard to quantitative outcome measurement, metabolism of the labeled tracers and protein binding. Methods: Palladium-mediated carbonylation using [C-11]carbon monoxide, 4,6-dichloro-2-iodo-3-methoxyphenol and (S)-(-)-2-aminomethyl-1-ethylpyrrolidine was applied in the synthesis of ([C-11]carbonyl)raclopride. The reaction was performed at atmospheric pressure using xantphos as supporting phosphine ligand and palladium (pi-cinnamyl) chloride dimer as the palladium source. ([C-11]Methyl)raclopride was prepared by a previously published method. In the PET study, two female cynomolgus monkeys were used under gas anesthesia of sevoflurane. A dynamic PET measurement was performed for 63 min with an HRRT PET camera after intravenous injection of ([C-11]carbonyl)raclopride and ([C-11]methyl)raclopride, respectively, during the same day. The order of injection of the two PET radioligands was changed between the two monkeys. The venous blood sample for measurement of protein binding was taken 3 min prior to the PET scan. Binding potential (BPND) of the putamen and caudate was calculated with SRTM using the cerebellum as a reference region. Results: The target compound ([C-11]carbonyl)raclopride was obtained with 50 +/- 5% decay corrected radiochemical yield and 95% radiochemical purity. The trapping efficiency (TE) of [C-11]carbon monoxide was 65 +/- 5% and the specific radioactivity of the final product was 34 +/- 1 GBq/mu mol after a 50 min of synthesis time. The radiochemical yield of ([C-11]methyl)raclopride was in the same range as published previously i.e. 50-60% and specific radioactivity of those two batches which were used in the present PET study were 192 GBq/mu mol and 638 GBq/mu mol respectively after a synthesis time of 32 min. In monkey PET studies, the percentage difference of BPND in putamen was <3% and that in caudate was <9% for the two radioligands. The plasma protein binding was 86.2 +/- 0.3% and 85.7 +/- 0.6% for ([C-11]carbonyl)raclopride and ([C-11]methyl)raclopride, respectively. The radiometabolite pattern was similar for both radioligands. Conclusion: Raclopride was C-11-labeled at the carbonyl position using a palladium-mediated [C-11]carbonylation reaction. A comparison between ([C-11]carbonyl)raclopride and ([C-11]merhyl)raclopride with regard to quantitative PET outcome measurements, metabolism of radioligands and protein binding in monkey was performed. The monkey PET study with ([C-11]carbonyl)raclopride showed similar results as for ([C-11]methyl)raclopride. The PET studies were performed on 2 subjects.
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| 4. |
- Schou, Magnus, et al.
(författare)
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Pulmonary PET imaging confirms preferential lung target occupancy of an inhaled bronchodilator
- 2019
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Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Positron emission tomography (PET) is a non-invasive molecular imaging technique that traces the distribution of radiolabeled molecules in experimental animals and human subjects. We hypothesized that PET could be used to visualize the binding of the bronchodilator drug ipratropium to muscarinic receptors (MR) in the lungs of living non-human primates (NHP). The objectives of this study were two-fold: (i) to develop a methodology for quantitative imaging of muscarinic receptors in NHP lung and (ii) to estimate and compare ipratropium-induced MR occupancy following drug administration via intravenous injection and inhalation, respectively.Methods: A series of PET measurements (n=18) was performed after intravenous injection of the selective muscarinic radioligand C-11-VC-002 in NHP (n=5). The lungs and pituitary gland (both rich in MR) were kept in the field of view. Each PET measurement was followed by a PET measurement preceded by treatment with ipratropium (intravenous or inhaled).Results: Radioligand binding was quantified using the Logan graphical analysis method providing the total volume of distribution (V-T). Ipratropium reduced the V-T in the lung and pituitary in a dose-dependent fashion. At similar plasma ipratropium concentrations, administration by inhalation produced larger reductions in V-T for the lungs. The plasma-derived apparent affinity for ipratropium binding in the lung was one order of magnitude higher after inhalation (K-iih=1.01nM) than after intravenous infusion (K-iiv=10.84nM).Conclusion: Quantitative muscarinic receptor occupancy imaging by PET articulates and quantifies the therapeutic advantage of the inhaled route of delivery and provides a tool for future developments of improved inhaled drugs.
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