[¹¹C]N-Methyl-N-phenyl-[2-(4-chlorophenyl)-6,8-dichloroimidazo[1,2-a]pyridin-3-yl]acetamide

[[¹¹C]PBR7]

Background

[PubMed]

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 receptors (CBRs) and peripheral benzodiazepine receptors (PBRs). 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 PBRs than do peripheral tissues. Both glial cells and macrophages contain high levels of PBRs (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 with 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 as been 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) has been 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 ligands with highly selective and specific binding to PBR. [¹¹C]N-Methyl-N-phenyl-[2-(4-chlorophenyl)-6,8-dichloroimidazo[1,2-a]pyridin-3-yl]acetamide ([¹¹C]PBR7, a partial agonist) with an imidazopyridine acetamide structure has been developed for imaging PBR (10, 11).

Synthesis

[PubMed]

Sekimata et al. (10) reported the synthesis of [¹¹C]PBR7 by ¹¹C-methylation of the N-desmethyl precursor with [¹¹C]iodomethane in the presence of NaH in dimethylformamide for 3 min at 80ºC. [¹¹C]PBR7 was purified with high-performance liquid chromatography. The specific activity was 20–150 GBq/μmol (0.54–4.05 Ci/μmol) with >98% radiochemical purity and a radiochemical yield of 36% (decay-corrected) at the end of synthesis.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

In vitro receptor binding studies showed that PBR7 had K_i values of 0.2 nM for PBR and >6,000 nM for CBR (11). PBR7 has a moderate lipophilicity (log P = 2.2). PK11195 exhibited a K_i value of 4.3 nM.

Animal Studies

Human Studies

[Pub Med]

No publications are currently available.

References