Development of Ligands for the Peripheral Benzodiazepine Receptor

Abstract

Abstract:The peripheral benzodiazepine receptor (PBR) initially characterised as a high affinity binding site for diazepam, is densely distributed in most peripheral organs whilst only moderately expressed in the healthy brain. The predominant cell type expressing the PBR at regions of central nervous system (CNS) pathology are activated microglial cells. Under neuroinflammatory conditions there is an over-expression of PBR binding sites indicating that measurements of PBR density can act as a useful index of brain disease activity. The PBR is now considered a significant therapeutic and diagnostic target which has provided the impetus for PBR ligand development. There are several classes of PBR ligands available including benzodiazepines (Ro5 -4864), isoquinoline carboxamides (PK 11195), indoleacetamides (FGIN-1-27), phenoxyphenyl-acetamides (DAA1106) and pyrazolopyrimidines (DPA-713). Subsequent conformationally restrained isoquinoline and indoleacetamide analogues have been synthesised in an attempt to yield PBR ligands with superior affinity and brain kinetics. Even though the PBR has been linked to a number of biochemical processes, including cell proliferation, apoptosis, steroidogenesis, porphyrin transport and immunomodulation, its exact physiological role is yet to be deciphered. Selective PBR ligands with favourable in vivo binding properties and kinetics is required to gain a more complete understanding on the normal functioning of the PBR and the chemical pathways underlying several pathological conditions. Novel PBR ligands with unique binding properties and functional activity may also generate information on the localisation of the PBR and the possibility of PBR subtypes. This review highlights the main classes of PBR ligands to date. In addition the biological activity and therapeutic potential of certain PBR ligands is discussed.

DPA-714, a New Translocator Protein–Specific Ligand: Synthesis, Radiofluorination, and Pharmacologic Characterization

“…Over the last decade, TSPO ligand development has yielded a multitude of new high-affinity compounds (34); however, the range of PET ligands for the TSPO remains limited. 11 C-PK11195 is still the most widely used PET tracer for TSPO studies, despite its deficiencies (19).…”

Imaging of Microglia Activation in Stroke

“…Эти радиолиганды относятся к разным классам химических соединений -бензодиазепинам, карбоксамидам хинолина, ацетамидам индола, алка-лоидам барвинка, оксодигидропуринам, феноксиари-лацетамидам и имидазопиридинам [5,10] -но лишь немногие из них используют в практике. Первым радио-активным индикатором, который до сих пор широко используется в исследованиях, является 11 C-PK 11195, хотя его применение сопряжено с многочисленными ограничениями [5]: высокий уровень неспецифическо-го связывания и низкое отношение сигнал-шум затруд-няет его количественную оценку, углерод-11 мечение (период полураспада 20,38 минут) ограничивает его клиническое применение, а количественная оценка соответствующих параметров, таких как кинетические константы и связывающий потенциал, осложняет-ся трудностями в определении истинной референ-сной области (т.е., области без рецепторов).…”

Translocator Protein (18 kDa) Polymorphism (rs6971) Explains in-vivo Brain Binding Affinity of the PET Radioligand [18F]-FEPPA

“…The first and most widely used radiotracer is [ 11 C]-PK11195 (Camsonne et al, 1984); however, this radiotracer has recognized limitations including high nonspecific binding, low brain penetration, high plasma protein binding, and a difficult synthesis. The deficiencies of [ 11 C]-PK11195 coupled with the recognized importance of TSPO imaging have fueled considerable efforts to develop radiotracers with greater sensitivity to detect TSPO binding (James et al, 2006;Okubo et al, 2004). While [ 11 C]-PBR28 (Fujita et al, 2008) and [ 11 C]-DPA713 (Boutin et al, 2007) circumvent many of the deficiencies of [ 11 C]-PK11195, both are radiolabeled with the short-lived carbon-11, rendering unsuitable for wide-spread dissemination.…”