Macrophage and Astrocyte Populations in Relation to [<sup>3</sup>H]PK 11195 Binding in Rat Cerebral Cortex following a Local Ischaemic Lesion

Myers, Ralph; Manjil, Luisa G.; Cullen, Beulah M.; Price, Gary; Frackowiak, R. S. J.; Cremer, Jill E.

doi:10.1038/jcbfm.1991.64

Cited by 168 publications

(113 citation statements)

References 28 publications

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“…21,27 Indeed, numerous experimental models have shown that autoradiographically detected PK11195 binding correlates better with the temporospatial profile of microglial activation than with that of reactive astrocytes. 18,19,28,29 Discrepancies with other reported cellular localization data using a polyclonal antibody 30 might hint to differences between the sites or PBR subunits recognized by the antibody and those to which (R)-PK11195 binds on tissue sections and in vivo. Cellular localization data from a model of chemically induced demyelination using cuprizone reported by the same group, indicate that in certain lesion-types, astrocytes, too, bind PK11195.…”

Section: Pk11195 Binding To Pbr: From In Vitro Ligand To In Vivo Pet mentioning

confidence: 97%

“…[17][18][19] Early studies of the functional role of the PBR were performed in astrocytes cell cultures, which express high levels of PBR in vitro. 20 As will be discussed shortly, however, these in vitro observations could not be fully extended to the in vivo state.…”

Section: Cellular Source and Functionmentioning

confidence: 99%

“…18,29 A longitudinal [ 11 C](R)-PK11195 PET study in patients after ischemic stroke 59 demonstrated that [ 11 C](R)-PK11195 binding was present after the first week in the ischemic border zone, with an early detection beyond 72 hours, 60 and later spread beyond this region into the thalamus and neocortex. The later involvement in regions connected by degenerating white matter tracts to the ischemic core, such as the ipsilateral thalamus via the damaged corticothalamic projections, 61 was due to microglial activation occurring along the neuronal pathways expected to develop Wallerian degeneration and may have a role in long-term plasticity and recovery.…”

Section: Imaging Neuroinflammation In Strokementioning

confidence: 99%

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Positron Emission Tomography Imaging of Neuroinflammation

et al. 2007

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In the diseased brain, upon activation microglia express binding sites for synthetic ligands designed to recognize the 18-kDa translocator protein TP-18, which is part of the so-called peripheral benzodiazepine receptor complex. PK11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide], the prototype synthetic ligand, has been widely used for the functional characterization of TP-18. Its cellular source in activated microglia has been established using high-resolution, single-cell autoradiography with the R-enantiomer [3H](R)-PK11195. Radiolabeled [11C](R)-PK11195 has been used to image active brain disease with positron emission tomography. Consistent with experimental and postmortem observations of a characteristically distributed pattern of microglia activation in areas of focal pathology, as well as in anterograde and retrograde projection areas, the in vivo regional [11C](R)-PK11195 signal is found in active focal lesions and over time also along the affected neural tracts and their respective cortical and subcortical projection areas. Thus, a profile of active disease emerges that matches some of the typical distribution patterns known from structural neuroimaging techniques, but additionally shows involvement of brain regions linked through neural pathways. In the context of cell-based in vivo neuropathology, the image data are thus best interpreted in the context of the emerging cellular understanding of brain disease or damage, rather than the definitions of clinical diagnosis. One important observation, borne out by experiment, is the long latency with which activated microglia or increased PK11195 retention appear to gradually emerge and remain in distal areas secondarily affected by disease, supporting speculations that the presence of activated microglia is an important corollary of brain plasticity

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Section: Pk11195 Binding To Pbr: From In Vitro Ligand To In Vivo Pet mentioning

confidence: 97%

Section: Cellular Source and Functionmentioning

confidence: 99%

Section: Imaging Neuroinflammation In Strokementioning

confidence: 99%

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Positron Emission Tomography Imaging of Neuroinflammation

et al. 2007

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“…In the future, [ 11 C]DAA1106 will be applied for various diseases, and in a case with low k 3 or k 4 , interpretation of the estimated BP would require some caution. The density of PBR was reported to increase in microglia activated by brain damages (Myers et al, 1991;Stephenson et al, 1995;Banati et al, 1997;Kuhlmann and Guilarte, 2000). Cagnin et al (2001) reported that the BP of Alzheimer's disease patients in the [ 11 C]PK11195 study was approximately twice the BP of controls in the inferior and middle temporal gyri, the inferior parietal lobules, and so on.…”

Section: Reliability Of Estimated Parameters With Nonlinear Least-squmentioning

confidence: 99%

Quantitative Analysis for Estimating Binding Potential of the Peripheral Benzodiazepine Receptor with [¹¹C]DAA1106

Ikoma¹,

Yasuno²,

Ito³

et al. 2007

J Cereb Blood Flow Metab

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[ 11 C]DAA1106 is a potent and selective ligand for the peripheral benzodiazepine receptor (PBR) with high affinity. It has been reported that the density of PBR is related to brain damage, so a reliable tracer method for the evaluation of PBR would be of use. We evaluated a quantification method of [ 11 C]DAA1106 binding in simulated data and human brain data. In the simulation study, the reliability of parameters estimated from the nonlinear least-squares (NLS) method, graphical analysis (GA), and multilinear analysis (MA) was evaluated. In GA, variation of the estimated distribution volume (DV) was small. However, DV was underestimated as noise increased. In MA, bias was smaller, and variation of the estimated DV was larger than in GA. In NLS, although variation was larger than in GA, it was small enough in regions of interest analysis, and not only DV but also binding potential (BP), determined from the k 3 /k 4 without any constraint, could be estimated. The variation of BP estimated with NLS became larger as k 3 or k 4 became smaller. In human studies with normal volunteers, regions of interest were drawn on several brain regions, BP was calculated by NLS, and DV was also estimated by NLS, GA, and MA. As a result, DVs estimated with each method were well correlated. However, there was no correlation between BP with NLS and DV with NLS, GA, and MA, because of the variation of K 1 /k 2 between individuals. In conclusion, BP is estimated most reliably by NLS with the two-tissue compartment model.

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“…11195, alongside immunohistochemistry, demonstrated that elevated PBR binding directly correlated with the appearance of activated microglia [26]. More recently, in vivo positron emission tomography (PET) imaging using [ 11 C]PK 11195 in patients suffering from Alzheimer's disease (AD) and multiple sclerosis (MS) It is generally accepted that an increase in PBR density is a reliable marker of microglial activation and neuroinflammation [34] and can therefore be used as an index of active disease in the brain.…”

Section: Introductionmentioning

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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Macrophage and Astrocyte Populations in Relation to [³H]PK 11195 Binding in Rat Cerebral Cortex following a Local Ischaemic Lesion

Cited by 168 publications

References 28 publications

Positron Emission Tomography Imaging of Neuroinflammation

Positron Emission Tomography Imaging of Neuroinflammation

Quantitative Analysis for Estimating Binding Potential of the Peripheral Benzodiazepine Receptor with [¹¹C]DAA1106

Development of Ligands for the Peripheral Benzodiazepine Receptor

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Macrophage and Astrocyte Populations in Relation to [3H]PK 11195 Binding in Rat Cerebral Cortex following a Local Ischaemic Lesion

Cited by 168 publications

References 28 publications

Positron Emission Tomography Imaging of Neuroinflammation

Positron Emission Tomography Imaging of Neuroinflammation

Quantitative Analysis for Estimating Binding Potential of the Peripheral Benzodiazepine Receptor with [11C]DAA1106

Development of Ligands for the Peripheral Benzodiazepine Receptor

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Product

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Macrophage and Astrocyte Populations in Relation to [³H]PK 11195 Binding in Rat Cerebral Cortex following a Local Ischaemic Lesion

Quantitative Analysis for Estimating Binding Potential of the Peripheral Benzodiazepine Receptor with [¹¹C]DAA1106