Radiosynthesis and initial evaluation of [18F]-FEPPA for PET imaging of peripheral benzodiazepine receptors.
ABSTRACT A novel [18F]-radiolabelled phenoxyanilide, [18F]-FEPPA, has been synthesized and evaluated, in vitro and ex vivo, as a potential positron emission tomography imaging agent for the peripheral benzodiazepine receptor (PBR).
[18F]-FEPPA and two other radiotracers for imaging PBR, namely [11C]-PBR28 and [11C]-PBR28-d3, were synthesised and evaluated in vitro and ex vivo as potential PBR imaging agents.
[18F]-FEPPA is efficiently prepared in one step from its tosylate precursor and [18F]-fluoride in high radiochemical yields and at high specific activity. FEPPA displayed a Ki of 0.07 nM for PBR in rat mitochondrial membrane preparations and a suitable lipophilicity for brain penetration (log P of 2.99 at pH 7.4). Upon intravenous injection into rats, [18F]-FEPPA showed moderate brain uptake [standard uptake value (SUV) of 0.6 at 5 min] and a slow washout (SUV of 0.35 after 60 min). Highest uptake of radioactivity was seen in the hypothalamus and olfactory bulb, regions previously reported to be enriched in PBR in rat brain. Analysis of plasma and brain extracts demonstrated that [18F]-FEPPA was rapidly metabolized, but no lipophilic metabolites were observed in either preparation and only 5% radioactive metabolites were present in brain tissue extracts. Blocking studies to determine the extent of specific binding of [18F]-FEPPA in rat brain were problematic due to large perturbations in circulating radiotracer and the lack of a reference region.
Further evaluation of the potential of [18F]-FEPPA will require the employment of rigorous kinetic models and/or appropriate animal models.
- European Neuropsychopharmacology 10/2013; 23:S451. · 5.40 Impact Factor
- European Neuropsychopharmacology 10/2013; 23:S450-S451. · 5.40 Impact Factor
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ABSTRACT: Adequate estimation of neuroinflammatory processes following ischemic stroke is essential for better understanding of disease mechanisms, and for the development of treatment strategies. With the TSPO (18 kDa translocator protein) positron emission tomography (PET) radioligand [(11)C]PBR28, we monitored longitudinally the inflammatory response post-transient cerebral ischemia in rats, using a recently developed rat stroke model that produces isolated focal cortical infarcts with clinical relevance in size and pathophysiology. Six Sprague-Dawley rats were subjected to 90 min transient endovascular occlusion of the M2 segment of the middle cerebral artery (M2CAO). Animals were imaged with a nanoScan(®) PET/MRI system at 1, 4, 7 and 14 days after M2CAO with a bolus injection of [(11)C]PBR28. In the infarct region, we found a significantly increased uptake of [(11)C]PBR28 on day 4, 7 and 14 compared to day 1 as well as compared to the contralateral cortex. No significant increase was detected in the contralateral cortex during the 14 days of imaging. The activation in the infarct region gradually decreased between day 4 and day 14. In an additional group of animals (n = 26), immunofluorescence studies were performed with antibodies for activated microglia/monocytes (Cd11b), phagocytes (Cd68), astrocytes (glial fibrillary acidic protein) and TSPO. The TSPO immunofluorescence signal indicated reactive microgliosis post injury, corresponding to PET findings. The present clinically relevant animal model and TSPO PET ligand appear to be well suited for studies on neuroinflammation after ischemic stroke.Brain Structure and Function 01/2015; · 7.84 Impact Factor