Alzheimer's disease (AD) is the most common cause of dementia. Neuroinflammation appears to play an important role in AD pathogenesis. Ligands of the 18 kDa translocator protein (TSPO), a marker for activated microglia, have been used as positron emission tomography (PET) tracers to reflect neuroinflammation in humans and mouse models. Here, we used the novel TSPO-targeted PET tracer 18 F-GE180 (flutriciclamide) to investigate differences in neuroinflammation between young and old WT and APP/PS1dE9 transgenic (Tg) mice. In vivo PET scans revealed an overt age-dependent elevation in whole-brain uptake of 18 F-GE180 in both WT and Tg mice, and a significant increase in whole-brain uptake of 18 F-GE180 (peak-uptake and retention) in old Tg mice compared with young Tg mice and all WT mice. Similarly, the 18 F-GE180 binding potential in hippocampus was highest to lowest in old Tg Ͼ old WT Ͼ young Tg Ͼ young WT mice using MRI coregistration. Ex vivo PET and autoradiography analysis further confirmed our in vivo PET results: enhanced uptake and specific binding (SUV 75% ) of 18 F-GE180 in hippocampus and cortex was highest in old Tg mice followed by old WT, young Tg, and finally young WT mice.18 F-GE180 specificity was confirmed by an in vivo cold tracer competition study. We also examined 18 F-GE180 metabolites in 4-month-old WT mice and found that, although total radioactivity declined over 2 h, of the remaining radioactivity, ϳ90% was due to parent 18 F-GE180. In conclusion, 18 F-GE180 PET scans may be useful for longitudinal monitoring of neuroinflammation during AD progression and treatment.
Microwave reactors remain largely underutilized in the field of PET chemistry. This is particularly unfortunate since microwave synthesis elegantly addresses two of the most critical issues of PET radiochemistry with short-lived radionuclides: reaction rate and side-product formation. In this study we investigate the efficiency of synthesis of terminally [ 18 F]fluorinated fatty acid analogs using a commercial microwave reactor in comparison with conventional heating.Methods-The labeling precursors were methyl esters of terminally substituted alkyl bromides and iodides. Duration and temperatures of the [ 18 F]fluorination reaction were varied. Chemical and radiochemical purities, and radiochemical yields were investigated for conventional (CH) and microwave-assisted (MW) radiosyntheses.Results-The results demonstrate that microwave heating enhanced [ 18 F]fluoride incorporation to >95% (up to 55% improvement), while reducing reaction times to 2 min (~10-fold reduction) or temperatures to 55-60°C (20°C reduction). Overall decay-corrected radiochemical yields of purified [ 18 F]fluoro fatty acids were higher (MW=49.0 ± 4.5%, CH=23.6 ± 3.5%, p<0.05) with microwave heating and side-products were notably fewer.Conclusion-For routine synthesis of [ 18 F]fluoro fatty acid analogs, microwave heating is faster, milder, cleaner, less variable and higher yielding than conventional heating and therefore the preferred reaction method.
Fatty acid oxidation (FAO) is a major energy-providing process with important implications in cardiovascular, oncologic, neurologic, and metabolic diseases. A novel 4-thia oleate analog, 18-18 F-fluoro-4-thia-oleate ( 18 F-FTO), was evaluated in relationship to the previously developed palmitate analog 16-18 Ffluoro-4-thia-palmitate ( 18 F-FTP) as an FAO probe. Methods: 18 F-FTO was synthesized from a corresponding bromoester. Biodistribution and metabolite analysis studies were performed in rats. Preliminary small-animal PET studies were performed with 18 F-FTO and 18 F-FTP in rats. Results: A practical synthesis of 18 F-FTO was developed, providing a radiotracer of high radiochemical purity (.99%). In fasted rats, myocardial uptake of 18 F-FTO (0.70 6 0.30% dose kg [body mass]/g [tissue mass]) was similar to that of 18 F-FTP at 30 min after injection. At 2 h, myocardial uptake of 18 F-FTO was maintained, whereas 18 F-FTP uptake in the heart was 82% reduced. Similar to 18 F-FTP, 18 F-FTO uptake by the heart was approximately 80% reduced at 30 min by pretreatment of rats with the CPT-I inhibitor etomoxir. Folch-type extraction analyses showed 70-90% protein-bound fractions in the heart, liver, and skeletal muscle, consistent with efficient trafficking of 18 F-FTO to the mitochondrion with subsequent metabolism to protein-bound species. Preliminary small-animal PET studies showed rapid blood clearance and avid extraction of 18 F-FTO and of 18 F-FTP into the heart and liver. Images of 18 F-FTO accumulation in the rat myocardium were clearly superior to those of 18 F-FTP. Conclusion: 18 F-FTO is shown to be a promising metabolically trapped FAO probe that warrants further evaluation.
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