Binding characteristics of DAA1106, a novel and selective ligand for peripheral benzodiazepine receptors

Chaki, Shigeyuki; Funakoshi, Takeo; Yoshikawa, Rokusuke; Okuyama, Shigeru; Okubo, Taketoshi; Nakazato, Atsuro; Nagamine, Masashi; Tomisawa, Kazuyuki

doi:10.1016/s0014-2999(99)00118-1

Cited by 77 publications

(56 citation statements)

References 19 publications

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“…9), were derived by opening the diazepine ring of Ro5-4864. They have since been reported as specific ligands for the PBR [68] and display potent anxiolytic effects in laboratory animals [69].…”

Section: Phenoxyphenyl-acetamide Derivativesmentioning

confidence: 99%

“…Autoradiographic and biochemical studies revealed that the highest density binding of [ 3 H]DAA1106 in the brain was in the olfactory bulb, followed by the cerebellum and cerebral cortex [68]. [2-(4-chlorophenyl)imidazo [1,2-a]pyridin-3-yl)]acetamide, although displaying high PBR affinity (5-10 nM), was the only reported 2-phenyl-imidazo[1,2-a]-pyridine that failed to have any effect on neuroactive steroid concentration in cerebral cortex and is thus considered to be an antagonist [66].…”

Section: Phenoxyphenyl-acetamide Derivativesmentioning

confidence: 99%

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Development of Ligands for the Peripheral Benzodiazepine Receptor

James¹,

Selleri²,

Kassiou

2006

CMC

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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.

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Section: Phenoxyphenyl-acetamide Derivativesmentioning

confidence: 99%

Section: Phenoxyphenyl-acetamide Derivativesmentioning

confidence: 99%

Development of Ligands for the Peripheral Benzodiazepine Receptor

James¹,

Selleri²,

Kassiou

2006

CMC

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“…Ligands that bind to PBR with higher affinity compared to PK11195 may show greater sensitivity in detecting milder forms of neuroinflammation. DAA1106 [N-(2,5-dimethoxybenzyl)-N-(4-uoro-2-phenoxyphenyl)-acetamide] is an aryloxyanilide derivative, that binds with higher affinity to PBR compared to PK11195 (Chaki et al, 1999, Maeda et al, 2004. We hypothesized that DAA1106 would label activated brain macrophages in encephalitic brain tissues with higher binding affinity when compared to that of PK11195.…”

Section: Introductionmentioning

confidence: 99%

The high affinity peripheral benzodiazepine receptor ligand DAA1106 binds to activated and infected brain macrophages in areas of synaptic degeneration: Implications for PET imaging of neuroinflammation in lentiviral encephalitis

Venneti

Wang

Wiley

2008

Neurobiology of Disease

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“…To characterize PBR precisely using a PET ligand with advantages over 11 C-PK11195, we developed 2 novel ligands, 11 C-DAA1106 (20,21) and 18 F-FEDAA1106 (22), for PBR imaging in the brain. These ligands exhibited more potent in vitro binding affinity for PBR than PK11195 and displayed remarkable selectivity against other receptors, including CBR (22)(23)(24). In vivo studies demonstrated that they had higher uptake and more specific binding in rodent and primate brains than 11 C-PK11195 (20)(21)(22).…”

mentioning

confidence: 99%

“…Second, the binding site for AC-5216 in the PBR domain might be closer to that for PK11195 than to those for other PBR ligands, such as Ro5-4864 (28). In addition to Ro5-4864, the binding site for DAA1106 in the PBR domain might have an extra component that does not interact efficiently with PK11195 (23,24). Third, AC-5216 has moderate lipophilicity; a mean cLogP (P is the octanol/ water partition coefficient) value of 3.5 was calculated with Pallas 3.4 software (Pallas GmbH), and a mean LogD (D is the octanol/water diffusion coefficient) value of 3.3 was measured in a phosphate buffer (pH 7.4):octanol system by the shaking flask method (n 5 3; maximum range, 65%).…”

mentioning

confidence: 99%