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, Sriram; Wang, Guoji; Wiley, Clayton A.

doi:10.1016/j.nbd.2007.08.016

Cited by 21 publications

(25 citation statements)

References 44 publications

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“…Nonetheless, our results are consistent with those by Venneti et al that showed no significant increase in TSPO radioligand binding in HIV+ individuals [52]. Wiley et al observed that HIV+ cognitively impaired individuals (post-HAART) did not show an increase in TSPO radioligand binding [52]; however, in both SIVE and HIVE, increased binding of TSPO radioligands were readily demonstrable [53,54]. Although these studies are not analogous to each other (clinical vs. pathological entities), this may be evidence that viral replication is playing a role in TSPO upregulation in HIV/SIV-infected brain.…”

Section: Discussionsupporting

confidence: 92%

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Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain

Cosenza-Nashat

Zhao

Suh

et al. 2009

Neuropathology Appl Neurobio

409

330

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Aims: Microglia are involved in neurodegeneration, are prime targets for anti‐inflammatory therapy and are potential biomarkers of disease progression. For example, positron emission tomography imaging employing radioligands for the mitochondrial translocator protein of 18 kDa (TSPO, formerly known as the peripheral benzodiazepine receptor) is being scrutinized to detect neuroinflammation in various diseases. TSPO is presumably present in activated microglia, but may be present in other neural cells. Methods: We sought to elucidate the protein expression in normal human central nervous system, several neurological diseases (HIV encephalitis, Alzheimer's disease, multiple sclerosis and stroke) and simian immunodeficiency virus encephalitis by performing immunohistochemistry with two anti‐TSPO antibodies. Results: Although the overall parenchymal staining was minimal in normal brain, endothelial and smooth muscle cells, subpial glia, intravascular monocytes and ependymal cells were TSPO‐positive. In disease states, elevated TSPO was present in parenchymal microglia, macrophages and some hypertrophic astrocytes, but the distribution of TSPO varied depending on the disease, disease stage and proximity to the lesion or relation to infection. Staining with the two antibodies correlated well in white matter, but one antibody also stained cortical neurones. Quantitative analysis demonstrated a significant increase in TSPO in the white matter of HIV encephalitis compared with brains without encephalitis. TSPO expression was also increased in simian immunodeficiency virus encephalitis. Conclusions: This report provides the first comprehensive immunohistochemical analysis of the expression of TSPO. The results are useful for informing the usage of positron emission tomography as an imaging modality and have an impact on the potential use of TSPO as an anti‐inflammatory pharmacological target.

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Section: Discussionsupporting

confidence: 92%

“…Wiley et al. observed that HIV+ cognitively impaired individuals (post‐HAART) did not show an increase in TSPO radioligand binding [52]; however, in both SIVE and HIVE, increased binding of TSPO radioligands were readily demonstrable [53,54]. Although these studies are not analogous to each other (clinical vs .…”

Section: Discussionmentioning

confidence: 98%

Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain

Cosenza-Nashat

Zhao

Suh

et al. 2009

Neuropathology Appl Neurobio

409

330

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“…CD68 is a lysosomal marker that labels CNS-resident activated microglia and macrophages that infiltrate into the brain from the periphery. Although immunohistochemical markers that can differentiate between these 2 cell populations in human brain tissues are not available, we have previously shown that PBR ligand binding does not differ in primary human activated microglia and macrophages (35). Overall, the present data suggest that both PBR ligands show increased binding corresponding mainly to activated microglia in human neurological disorders but that DAA1106 may be more useful for PET imaging.…”

Section: Discussionmentioning

confidence: 99%

The Positron Emission Tomography Ligand DAA1106 Binds With High Affinity to Activated Microglia in Human Neurological Disorders

Venneti

Wang

Nguyen

et al. 2008

J Neuropathol Exp Neurol

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110

189

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Chronic microglial activation is an important component of many neurological disorders, and imaging activated microglia in vivo will enable the detection and improved treatment of neuroinflammation. 1-(2-Chlorphenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carbox-amide (PK11195), a peripheral benzodiazepine receptor ligand, has been used to image neuroinflammation, but the extent to which PK11195 binding distinguishes activated microglia and reactive astrocytes is unclear. Moreover, PK11195 may lack sufficient sensitivity for detecting mild neuroinflammation. We hypothesized that N-(2,5-dimethoxybenzyl)-N-(4-fluoro-2-phenoxyphenyl) acetamide (DAA1106), a new ligand that binds specifically to peripheral benzodiazepine receptor, binds to activated microglia in human neurological diseases with higher affinity than does PK11195. We therefore compared the pharmacological binding properties of [3H](R)-PK11195 and [3H]DAA1106 in postmortem tissues from patients with cerebral infarcts, amyotrophic lateral sclerosis, Alzheimer disease, frontotemporal dementia, and multiple sclerosis (n = 10 each). In all diseases, [3H]DAA1106 showed a higher binding affinity as reflected by lower dissociation constant (KD) values than that of [3H](R)-PK11195. Moreover, specific binding of both ligands correlated with the presence of activated microglia identified by immunohistochemistry in situ. We conclude that 1) ligands that bind peripheral benzodiazepine receptor mainly label activated microglia in human neurological disorders and that 2) DAA1106 may possess binding characteristics superior to those of PK11195, which may be beneficial for in vivo positron emission tomography imaging.

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“…The PBR ligand PK11195 has undergone development as an agent for assessing macrophage and microglial activation in neurological disease for nearly 2 decades 11,25–28. More than a dozen years ago, Groom et al29 used PET with fludeoxyglucose F 18 and [ 11 C]( R , S )-PK11195 to compare PBR expression and cortical glucose metabolism in 8 patients with AD vs those of a control subject.…”

Section: Commentmentioning

confidence: 99%

Carbon 11–Labeled Pittsburgh Compound B and Carbon 11–Labeled (R)-PK11195 Positron Emission Tomographic Imaging in Alzheimer Disease

et al. 2009

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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

Abstract: HIV encephalitis (HIVE) is characterized by neurodegeneration mediated by toxins derived from infected and activated brain macrophages. Since the peripheral benzodiazepine receptor (PBR) is abundant on brain macrophages, we hypothesized that

Cited by 21 publications

References 44 publications

Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain

Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain

The Positron Emission Tomography Ligand DAA1106 Binds With High Affinity to Activated Microglia in Human Neurological Disorders

Carbon 11–Labeled Pittsburgh Compound B and Carbon 11–Labeled (R)-PK11195 Positron Emission Tomographic Imaging in Alzheimer Disease

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