N-(6-[F]Fluoro-4-phenoxypyridin-3-yl)-N-(2-methoxybenzyl)acetamide

The 18-kDa translocator protein (TSPO; also known as the peripheral benzodiazepine receptor (PBR)) is evolutionarily conserved and is found mainly in the outer membrane of the mitochondria of steroid-synthesizing tissues, including the brain (1). Although the TSPO is involved in neuroinflammation and axonal regeneration after brain injury (2), the best characterized function of this protein is the transport of cholesterol from the outer membrane of the mitochondria to the inner membrane of these organelles, where it is used for steroid and neurosteroid hormone synthesis (2). Very low levels of TSPO are expressed in healthy brain tissue, but, in the event of an injury, the protein is overexpressed at the site of injury (3) both in the peripheral nervous system (in Schwann cells, macrophages, and neurons) and in the central nervous system (in activated microglia and infiltrating macrophages) (1). In addition, TSPO is overexpressed in different types of neuroinflammatory diseases such as Alzheimer’s disease, Parkinson’s disease, stroke, and various cancers, including those of the brain (3), but the expression of this protein is downregulated in psychiatric disorders such as anxiety, schizophrenia, depression, and bipolar disorder (1). Because the TSPO density is altered during neuronal injury or disease, it has been suggested that TSPO may serve as a biomarker of neuroinflammation and may be used to determine the efficacy of drugs used to monitor the progression and treatment of neuroinflammatory diseases (3). Several TSPO-selective ligands with diverse chemical structures have been synthesized, radiolabeled with C or F, and evaluated with positron emission tomography (PET) for the noninvasive imaging of this receptor in the brain of various species of animals (mouse, rat, and monkey) (4). For a detailed discussion of the chemistry of different TSPO ligands, see Dolle et al. (3). It is not clear, however, how the labeled ligands interact with the TSPO, and much is unknown about the changes that take place within this protein during neuroinflammation and related disorders (5). [C]PK11195 targets TSPO and is commonly used with PET for the imaging of neurological disorders, but its uptake in the brain can be difficult to quantify because the tracer has high lipophilicity and exhibits high nonspecific binding (6). Much effort has been devoted to develop and screen new tracers that can be used for the imaging and quantification of TSPO (such as [C]DAA1106, [F]DAA1106, [F]FEDAA1106, [C]PBR28, etc.) (4, 6). However, these radioligands have to be synthesized with multi-step procedures, and all of them are still under investigation for use in animals (4). Using a single-step procedure, Damont et al. synthesized N-(6-[F]fluoro-4-phenoxypyridin-3-yl)-N-(2-methoxybenzyl)acetamide (6-[F]Fluoro-PBR28), a radiofluorinated derivative of PBR28, studied its characteristics , and evaluated the tracer for the imaging of TSPO in the rat brain (4).