Evaluation of three quinoline-carboxamide derivatives as potential radioligands for the in vivo pet imaging of neurodegeneration

Belloli, Sara; Moresco, Rosa María; Matarrese, Mario; Biella, Gabriele; Sanvito, Francesca; Simonelli, Pasquale; Turolla, E; Olivieri, Stefano; Cappelli, Andrea; Vomero, Salvatore; Galli-Kienle, M.; Fazio, Ferruccio

doi:10.1016/j.neuint.2003.08.006

Cited by 56 publications

(51 citation statements)

References 31 publications

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“…However, once assessed in vivo, these derivatives did not display improved affinity or kinetics compared to PK 11195 [34].…”

Section: Benzodiazepinesmentioning

confidence: 91%

“…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]. 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].…”

Section: Benzothiazepinesmentioning

confidence: 99%

“…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. For that reason the development of novel PBR ligands is important not only for therapeutic applications but they can also provide a means for assessing alterations in PBR density.…”

Section: Introductionmentioning

confidence: 99%

“…Since then, a variety of structurally related classes have been developed including the benzothiazepines and the benzoxazepines. Another class of PBR ligands, structurally unrelated to the benzodiazepines, are the isoquinolines from which PK 11195 is currently the most widely use PBR ligand [34] and regarded as the gold standard. Numerous other classes have been developed, however most are riddled with factors which limit their use in characterising the PBR in vivo.…”

Section: Introductionmentioning

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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“…However, once assessed in vivo, these derivatives did not display improved affinity or kinetics compared to PK 11195 [34].…”

Section: Benzodiazepinesmentioning

confidence: 91%

Section: Benzothiazepinesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Development of Ligands for the Peripheral Benzodiazepine Receptor

James¹,

Selleri²,

Kassiou

2006

CMC

View full text Add to dashboard Cite

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“…Guylas et al 70,71 have investigated [ 11 C]vinpocetine using PET, but only in healthy subjects or monkeys, and pharmacologic data indicate that vinpocetine may bind to binding sites other than the PBR. Belloli et al 72 have evaluated carbon-11 labeled VC193M, VC195, and VC198M in a rat model of striatal damage (quinolinic acid), and their in vivo distribution by microdissection of the brain. In these experiments, similar results were obtained when using either PK11195 or VC195.…”

Section: New Pbr Ligands For Pet Studies Of Microglial Activationmentioning

confidence: 99%

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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Translocator protein (18 kDa) is involved in the regulation of reactive gliosis

Veiga

Carrero

Pernía

et al. 2007

Glia

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Translocator protein (18 kDa) (TSPO), previously known as peripheral‐type benzodiazepine receptor, is a critical component of the mitochondrial permeability transition pore. Brain inflammation results in the induction of the expression of TSPO in glial cells and some TSPO ligands decrease reactive gliosis after brain injury. However, since some TSPO ligands are neuroprotective, their effects on reactive gliosis may be the consequence of a reduced neurodegeneration. To assess whether TSPO ligands can modulate reactive gliosis in absence of neuronal death, we have tested their effects on the inflammatory response induced in the hippocampus of male rats by the intracerebroventricular infusion of lipopolysaccharide (LPS). LPS treatment did not induce neuronal death, assessed by Fluoro jade‐B staining, but increased the number of cells immunoreactive for vimentin and MHC‐II, used as markers of reactive astrocytes and reactive microglia, respectively. Furthermore, LPS produced an increase in the number of proliferating microglia. The TSPO ligand PK11195 reduced the number of MHC‐II immunoreactive cells and the proliferation of microglia in LPS treated rats. In contrast, another TSPO ligand, Ro5‐4864, did not significantly affect the response of microglia to LPS. Neither PK11195 nor Ro5‐4864 affected the LPS‐mediated increase in the number of vimentin‐immunoreactive astrocytes at the time point studied, although PK11195 reduced vimentin immunoreactivity. These findings identify TSPO as a potential target for controlling neural inflammation, showing that the TSPO ligand PK11195 may reduce microglia activation by a mechanism that is independent of the regulation of neuronal survival. © 2007 Wiley‐Liss, Inc.

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Evaluation of three quinoline-carboxamide derivatives as potential radioligands for the in vivo pet imaging of neurodegeneration

Cited by 56 publications

References 31 publications

Development of Ligands for the Peripheral Benzodiazepine Receptor

Development of Ligands for the Peripheral Benzodiazepine Receptor

Positron Emission Tomography Imaging of Neuroinflammation

Translocator protein (18 kDa) is involved in the regulation of reactive gliosis

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