The peripheral benzodiazepine receptor ligand PK11195 binds with high affinity to the acute phase reactant α1-acid glycoprotein: implications for the use of the ligand as a CNS inflammatory marker

Lockhart, Andrew; Davis, Bill; Matthews, Julian C.; Rahmoune, Hassan; Hong, Guizhu; Gee, Antony D.; Earnshaw, David L.; Brown, John

doi:10.1016/s0969-8051(02)00410-9

Cited by 99 publications

(96 citation statements)

References 25 publications

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“…Such a discrepancy could be explained by differences in systemic infection with variation in non-CNS macrophage proliferation and subsequent specific binding of A recent report by Lockhart et al (50) has shown that the concentration of PBR sites in the whole blood of healthy human volunteers to be on the order of 10 nM, with approximately 85% of the ligand bound in plasma and 15% bound to blood cells. These investigators demonstrated that [ 11 C](R)-PK11195 binds with high affinity to α1-acid glycoprotein (AGP), which is present in varying degrees in serum.…”

Section: Discussionmentioning

confidence: 99%

PET imaging of brain macrophages using the peripheral benzodiazepine receptor in a macaque model of neuroAIDS

Venneti¹,

Lopresti²,

Wang³

et al. 2004

J. Clin. Invest.

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Section: Discussionmentioning

confidence: 99%

PET imaging of brain macrophages using the peripheral benzodiazepine receptor in a macaque model of neuroAIDS

Venneti¹,

Lopresti²,

Wang³

et al. 2004

J. Clin. Invest.

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“…Despite the frequent use of PK 11195, it has been shown to have a low brain permeability and highly variable kinetic behaviour. For these reasons, the sensitivity of PK 11195 in assessing and studying the PBR is significantly limited [54]. These poor characteristics have been attributed to the high lipophilicity and low bioavailability of PK 11195 (88% bound to plasma protein) [34].…”

Section: Benzothiazepinesmentioning

confidence: 99%

“…These poor characteristics have been attributed to the high lipophilicity and low bioavailability of PK 11195 (88% bound to plasma protein) [34]. Although these issues are still under debate, binding studies revealed that α1-acid glycoprotein (AGP) is the primary plasma protein to which PK 11195 binds [54]. Since plasma AGP levels vary between individuals, especially in individuals with underlying pathological diseases, the level of free PK 11195 in the plasma can be unpredictable and thus may contribute to the inconsistent kinetic behaviour of this ligand.…”

Section: Benzothiazepinesmentioning

confidence: 99%

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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“…11 C-(R)-PK11195 has long been considered the standard for TSPO imaging; however, its poor signal-to-noise ratio and low brain permeability limit its accuracy and usefulness (19). Several new TSPO-specific ligands, namely, 11 C-DAA1106, 18 F-FEDAA1106, and 11 C-PBR28, have been described and reported to display good in vivo properties in rodent brains (20,21).…”

mentioning

confidence: 99%

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

James

Fulton²,

Vercouillie³

et al. 2008

J Nucl Med

249

251

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The translocator protein (18 kDa) (TSPO), formerly known as the peripheral benzodiazepine receptor, is dramatically upregulated under pathologic conditions. Activated microglia are the main cell type expressing the TSPO at sites of central nervous system pathology. Radioligands for the TSPO can therefore measure active disease in the brain. This article details the synthesis, radiofluorination, and pharmacologic evaluation of a new TSPOspecific pyrazolopyrimidine, DPA-714. Methods: The affinity of DPA-714 for the TSPO was measured in rat kidney membranes with 3 H-PK11195. The in vitro functional activity of DPA-714 was measured in a steroidogenic assay in which the ability of DPA-714 to increase pregnenolone synthesis was measured with rat C6 glioma cells. The radiofluorination of DPA-714 was achieved by nucleophilic 18 F-fluoride displacement of the tosylate precursor. 18 F-DPA-714 was assessed in rats harboring unilateral quinolinic acid (QA) lesions. In addition, pretreatment experiments were performed with PK11195 (5 mg/kg), DPA-714 (1 mg/kg), and DPA-713 (1 mg/kg). The in vivo binding and biodistribution of 18 F-DPA-714 were determined in a baboon with PET. Experiments involving presaturation with PK11195 (1.5 mg/kg) and displacement with DPA-714 (1 mg/kg) were conducted to evaluate the specificity of radioligand binding. Results: In vitro binding studies revealed that DPA-714 displayed a high affinity for the TSPO (dissociation constant, 7.0 nM). DPA-714 stimulated pregnenolone synthesis at levels 80% above the baseline. 18 F-DPA-714 was prepared at a 16% radiochemical yield and a specific activity of 270 GBq/mmol. In rats harboring unilateral QA lesions, an 8-fold-higher level of uptake of 18 F-DPA-714 was observed in the ipsilateral striatum than in the contralateral striatum. Uptake in the ipsilateral striatum was shown to be selective because it was inhibited to the level in the contralateral striatum in the presence of PK11195, nonlabeled . PET studies demonstrated rapid penetration and good retention of 18 F-DPA-714 in the baboon brain. Pretreatment with PK11195 effectively inhibited the uptake of 18 F-DPA-714 in the whole brain, indicating its selective binding to the TSPO. The injection of nonlabeled DPA-714 20 min after the injection of 18 F-DPA-714 resulted in radioligand washout, demonstrating the reversibility of 18 F-DPA-714 binding. Conclusion: 18 F-DPA-714 is a specific radioligand for the TSPO, displaying promising in vivo properties and thus warranting further investigation.

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The peripheral benzodiazepine receptor ligand PK11195 binds with high affinity to the acute phase reactant α1-acid glycoprotein: implications for the use of the ligand as a CNS inflammatory marker

Cited by 99 publications

References 25 publications

PET imaging of brain macrophages using the peripheral benzodiazepine receptor in a macaque model of neuroAIDS

PET imaging of brain macrophages using the peripheral benzodiazepine receptor in a macaque model of neuroAIDS

Development of Ligands for the Peripheral Benzodiazepine Receptor

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

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