The Peripheral Benzodiazepine Receptor: A Promising Therapeutic Drug Target

Abstract

The peripheral benzodiazepine receptor (PBR) is a critical component of the mitochondrial permeability transition pore (MPTP), a multiprotein complex located at the contact site between inner and outer mitochondrial membranes, which is intimately involved in the initiation and regulation of apoptosis. PBR is a small evolutionary conserved protein, located at the surface of the mitochondria where it is physically associated with the voltage-dependent anion channel (VDAC) and adenosine nucleotide translocase (ANT) that form the backbone of MPTP. PBR is widely distributed throughout the body and has been associated with numerous biological functions. Consistent with its localization in the MPTP, PBR is involved in the regulation of apoptosis, but also in the regulation of cell proliferation, stimulation of steroidogenesis, immunomodulation, porphyrin transport, heme biosynthesis, anion transport and regulation of mitochondrial functions. The recent literature on PBR is reviewed here. Specifically, we highlight numerous results suggesting that the use of specific PBR ligands to modulate PBR activity may have potential therapeutic applications and might be of significant clinical benefit in the management of a large spectrum of different indications including cancer, auto-immune, infectious and neurodegenerative diseases. In addition, we present the proposed mechanisms by which the molecules exerted these effects, particularly oriented on the modulation of the MPTP activities.

Brain and whole-body imaging in nonhuman primates of [11C]PBR28, a promising PET radioligand for peripheral benzodiazepine receptors

“…Brain uptake of [ 11 C]-(R)-PK 11195 increases in several acute neurological and neurodegenerative disorders associated with inflammation (Galiegue et al, 2003). Recently, a new class of aryloxyanalide-based radioligands have been developed , and they have 4 to 18 times greater affinity for PBRs than PK 11195 .…”

Synthesis, Characterization, and in Vitro Evaluation of a New TSPO-Selective Bifunctional Chelate Ligand

“…Such a strategy is commonly reported as bifunctional chelate (BFC) approach. 20 Hence, starting from the already known potent and selective TSPO ligand CB86 (Chart 1), 15 we designed a new namely,[2][3][4][5][6][7][8] 1), where, the di(2-picolyl)amine moiety could be used for the synthesis of coordination complexes containing a metallo drug to be used in diagnosis and therapy.Preliminarily, we performed in vitro studies on the newly synthesized TSPO-selective BFC ligand CB256 in order to assess its affinity toward TSPO. In addition, since it is wellknown that TSPO ligands are able to induce apoptosis, we also investigated the cytotoxic activity and the ability to cause morphological changes of the mitochondrion and of the nucleus, the collapse of the mitochondrial membrane potential (ΔΨ m ), and alterations of the cell cycle progression in C6…”

“…Such a strategy is commonly reported as bifunctional chelate (BFC) approach. 20 Hence, starting from the already known potent and selective TSPO ligand CB86 (Chart 1), 15 we designed a new namely,[2][3][4][5][6][7][8] 1), where, the di(2-picolyl)amine moiety could be used for the synthesis of coordination complexes containing a metallo drug to be used in diagnosis and therapy.…”

Targeting Neuroprotection as an Alternative Approach to Preventing and Treating Neuropathic Pain

“…[142][143][144] SSR180575 (7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-b]indole-1-acetamide) is a novel specific and potent TSPO ligand improving functional recovery in rat models of peripheral neuropathy. 145,146 SSR180575 increased pregnenolone accumulation in the brain and sciatic nerve (100% increase at 3 mg/kg, i.p.…”