368 research outputs found

    [11C]phosgene: Synthesis and application for development of PET radiotracers

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    Carbon-11-labeled phosgene ([11C]phosgene, [11C]COCl2) is a useful labeling agent that connects two heteroatoms by inserting [11C]carbonyl (11C=O) function in carbamates, ureas, and carbonates, which are components of biologically important heterocyclic compounds and functional groups in drugs as a linker of fragments with in vivo stability. Development of 11C-labeled PET tracers has been performed using [11C]phosgene as a labeling agent. However, [11C]phosgene has not been frequently used for 11C-labeling because preparation of [11C]phosgene required dedicated synthesis apparatus (not commercially available) and had problems in reproducibility and reliability. In our laboratory, an improved method for synthesizing [11C]phosgene using a carbon tetrachloride detection tube kit in environmental air analysis and the automated synthesis system for preparing [11C]phosgene have been developed in 2009. This apparatus has been used for routine synthesis of 11C-labeled tracers 1–4 times/week. Using [11C]phosgene we have developed and produced many PET radiotracers containing [11C]urea and [11C]carbamate moieties. In this review, we report the performance of our method for preparing [11C]phosgene, including automated synthesis apparatus developed in house, and the application of [11C]phosgene for development and production of 11C-labeled PET tracers

    Quantitative analysis of amyloid deposition in alzheimer disease using PET and [C-11]AZD2184

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    Objectives: Characteristic neuropathologic changes in Alzheimer disease (AD) are amyloid-beta deposits and neurofibrillary tangles. Carbon-11-labeled 5-(6-{[tert-butyl (dimethyl) silyl]oxy}-1,3-benzothiazol-2-yl) pyridin-2-amine ([C-11]AZD2184) is a more recently developed radiotracer for amyloid-beta deposits. [C-11]AZD2184 has high affinity in vitro for amyloid fibrils (dissociation constant, KD: 8.4 +- 1.0 nM) [1]. After intravenous injection of [C-11]AZD2184, there was rapid uptake of radioactivity in the brain followed by rapid washout in control subjects as well as in AD patients in an initial human study [2]. In this study, [C-11]AZD2184 binding in control subjects and AD patients was examined in more detail by compartment model analysis using a metabolite-corrected arterial input function. The accuracy of simplified quantitative methods employing a reference brain region was also evaluated. Methods: After intravenous bolus injection of [C-11]AZD2184, a dynamic PET scan was performed for 90 minutes in 6 control subjects and 8 AD patients. To obtain the arterial input function, arterial blood sampling and HPLC analysis were performed. To interpret the kinetic behaviour of [C-11]AZD2184, the standard two-tissue compartment model with four first-order rate constants (K1, k2, k3 and k4) was employed. The rate constants were estimated by non-linear curve fitting which was performed in a least-squares sense to the regional time-activity curves. Since the cerebellum can be used as a reference brain region, the total distribution volume ratio (DVR) of brain regions to cerebellum. In addition, the standardized uptake value ratio (SUVR) of brain regions to cerebellum obtained from integrated time-activity curves with integration intervals of 20-40 min, 40-60 min, and 60-90 min were calculated as the indicator of amyloid-beta deposits. Results: Time-activity curves in all brain regions could be described using the standard two-tissue compartment model. Binding potentials (BPND, equal to k3/k4) in cerebral cortical regions were higher in AD patients than in control subjects (AD patients: 2.0-2.3, control subjects: 1.0-1.1). Although there was no conspicuous accumulation of radioactivity in white matter as compared with other amyloid radioligands, BPND values were identified by compartment model analysis of the centrum semiovale for both control subjects and AD patients (about 1.7), suggesting binding to myelin. SUVR with each integration interval was in good agreement with DVR (AD patients: 1.8-2.6, control subjects: 1.0-1.2). Conclusions: It has been estimated that regions-of-interest defined for the cerebral cortex contain about 60% of gray matter and 30% of white matter [3]. This tissue heterogeneity may be one reason for the BPND values of [C-11]AZD2184 in cerebral cortical regions for control subjects. Although the white matter binding of [C-11]AZD2184 may have some effect on cortical uptake, it can be concluded that the kinetic behavior of [C-11]AZD2184 is suitable for quantitative analysis. SUVR can be used as a validated measure of [C-11]AZD2184 binding in clinical investigations without arterial input function. References: [1] Johnson AE, et al. J Neurochem 2009; 108: 1177-1186. [2] Nyberg S, et al. Eur J Nucl Med Mol Imaging 2009; 36: 1859-1863. [3] Ito H, et al. Neuroimage 2008; 39: 555-565.Brain & BrainPET 201