Radiosynthesis and initial evaluation of [18F]-FEPPA for PET imaging of peripheral benzodiazepine receptors

PET Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada M5T 1R8.
Nuclear Medicine and Biology (Impact Factor: 2.41). 05/2008; 35(3):305-14. DOI: 10.1016/j.nucmedbio.2007.12.009
Source: PubMed


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.

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    • "PK11195 is a ligand of TSPO, and carbon-11 labeled PK11195 (11C-PK11195) is a PET radiotracer that has been used for more than 20 years to quantify TSPO expression in the brain [92, 94]. Nevertheless, it has limitations such as high nonspecific binding and new tracers such as 11C-PBR28 [97], 11C-DPA713 [98], and 18F-FEPPA [99] are under investigation. "
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    • "Numerous radiolabeled TSPO ligands have been developed and evaluated in animal models of disease and in humans; of these [11C]PK11195 is the ligand most extensively studied [10], [11]. Several other ligands with improved properties (e.g. higher affinity, lower lipophilicity) have been described including [11C]vinpocetin [12], [18F]FMDAA1106, [18F]FEDAA1106 [13], [123I]CLINDE [14], [11C]CLINME [15], [18F]FEPPA or [18F]PBR28 [16], [11C]DAC [17], and [11C]DAA1106 [18]. The pyrazolopyrimidine [18F]DPA-714 was introduced in 2008 by James and colleagues as a highly specific new radioligand for TSPO with improved imaging properties over [11C]PK11195 [19]. "
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    • "Radiochemistry Details of [ 18 F]-FEPPA synthesis has been described elsewhere (Wilson et al, 2008). It is reliably and quickly labeled with [ 18 F] by nucleophilic displacement of a tosylate leaving group in a fast one-step reaction, yielding a sterile, pyrogen-free product after purification and formulation. "
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