Peripheral-type benzodiazepine receptor (PBR, TSPO), which was initially found in peripheral organs such as the kidney, nasal epithelium, lung, heart, and endocrine organs (i.e., the adrenal, testis, and pituitary glands) was subsequently found in the central nervous system (CNS) (1). PBR is mainly located in the glial cells of the brain, and PBR expression in vivo was increased in microglia activated by brain injury (1). The increase of PBR density has thus been used as an indicator of neuronal damage and neurodegenerative disorders such as Alzheimer’s disease (1).
PBR has been studied with in vivo positron emission tomography (PET) using [11C]PK11195. However, the relatively low uptake of [11C]PK11195 into the brain limited its wide application. To characterize PBR precisely using a PET ligand with improved behaviors compared to [11C]PK11195, [11C]DAA1106 (2) and [18F]FEDAA1106 (3) were developed for PBR imaging in the brain. In vivo study demonstrated that they had higher uptakes and better specific binding in rodent and primate brains than [11C]PK11195 (2, 3). Now, [11C]DAA1106 and [18F]FEDAA1106 are used to investigate PBR in the human brain to elucidate the relationship between PBR and brain diseases (4, 5). Subsequently, [11C]PBR28 and [11C]PBR06 (6), two analogs of [11C]DAA1106, were developed to localize and qualify upregulated PBR associated with cerebral ischemia in rats.
N-Benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide (AC-5216) was found to be a selective agonist for studying PBR in the central nervous system (7). AC-5216 had higher affinity for PBR prepared from rat brain than PK11195. AC-5216 also exhibited negligible activity for central benzodiazepine receptors (CBR) and a large number of other receptors, monoamine transporters, and ion channels. Moreover, the binding site of AC-5216 in the PBR domain might be closer to that of PK11195 than those of other PBR ligands. AC-5216 labeled with 11C ([11C]AC-5216) is being developed as a potent PET agent for the non-invasive study of microglia and macrophage activation relative to PBR in the brain (8-10).