N-(5-Fluoro-2-phenoxyphenyl)- N-(2-[131I]iodo-5-methoxybenzyl)acetamide

Excerpt

Benzodiazepines are potent psychoactive drugs used for their sedative and anxiolytic properties (1, 2). There are two types of benzodiazepine receptors, which have been designated as the central benzodiazepine receptor (CBR) and the peripheral benzodiazepine receptor (PBR). The CBR is found exclusively in the central nervous system on the membranes of neurons and is coupled to the γ-aminobutyric acid receptor/chloride channel (3). In contrast, the PBR is a mitochondrial protein found in brain and peripheral tissues (adrenal gland, heart, lung, kidney, and testis) (4). The brain has lower levels of PBR than do the peripheral tissues. Both glial cells and macrophages contain high levels of PBR (5-7). Increased PBR expression after brain injury or neuroinflammation is associated with microglial activation, such as occurs with the neuronal damage that accompanies several neurodegenerative diseases, including Alzheimer’s disease, Wernicke’s encephalopathy, multiple sclerosis, and epilepsy.

PBRs have been studied in vivo by positron emission tomography (PET) using 1-(2-chlorophenyl)-N-[¹¹C]methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide ([¹¹C]PK11195), an isoquinoline carboxamide with specific PBR-antagonistic activity. [¹¹C]PK11195 is being developed as a PET agent for non-invasive studies of microglia and macrophage activation in the brain, lung, and heart. However, accumulation of this tracer in the brain is limited. N-(2,5-Dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide (DAA1106) was found to be a selective agonist for studying PBRs in the central nervous system (8, 9). DAA1106 was reported to have a higher affinity for PBRs in mitochondrial fractions of rat and monkey brains than did PK11195 (8, 9). Therefore, both tracers are able to cross the normal cell membrane to reach the mitochondrial receptor sites. N-(5-Fluoro-2-phenoxyphenyl)-N-(2-[¹⁸F]fluoroethyl-5-methoxybenzyl)acetamide ([¹⁸F]FEDAA1106) and [¹¹C]DAA1106 have been developed as potential PET probes with highly selective and specific binding to PBR. N-(5-Fluoro-2-phenoxyphenyl)-N-(2-[¹³¹I]iodo-5-methoxybenzyl)acetamide ([¹³¹I]PBR3a), a DAA1106 analog, has been developed for single-photon emission computed tomography (SPECT) imaging of PBR in the brain.