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Benzodiazepines: Anticonvulsant and other clinical uses
Published in Adam Doble, Ian L Martin, David Nutt, Calming the Brain: Benzodiazepines and related drugs from laboratory to clinic, 2020
Adam Doble, Ian L Martin, David Nutt
In Chapter 2, it was mentioned that the binding of ligands for the peripheral benzodiazepine binding site in brain tissue has been used as a marker for gliosis following brain injury. The development of PET ligands for this site, notably [C]-PK 11195 (Charbonneau et al, 1986), has allowed this to be evaluated in man, with the intention of using this technique as a diagnostic tool. [C]-PK 11195 binding has been reported to be elevated in gliomas and astrocytomas (Starosta-Rubinstein et al, 1987; Junck et al, 1989; Pappata et al, 1991), and much interest has been shown in the use of this technique as a diagnostic marker for some such tumours. It should be noted, however, that the density of peripheral benzodiazepine binding sites on CNS tumours of different origins varies considerably (Cornu et al, 1992), which may restrict the use of this technology. Although two groups have reported the appearance of [C]-PK 11195 binding sites around the infarct site in stroke patients (Junck et al, 1990; Weiller et al, 1991), fewer data are available at present concerning the potential of PET studies with [C]-PK 11195 to evaluate the extent of lesions in neurodegenerative disease. Studies in animals would suggest that this technique could be a valuable diagnostic aid in a number of such illnesses, for example, multiple sclerosis.
Nuclear Imaging of the Vulnerable Plaque: Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET)
Published in Levon Michael Khachigian, High-Risk Atherosclerotic Plaques, 2004
John Davies, James Rudd, Tim Fryer, Jonathan Gillard, Peter Weissberg
Finally, because [18F]FDG is taken up by all metabolically active tissues including myocardium, it cannot be used to image coronary atheroma. This will require a more macrophage-specific ligand than [18F]FDG. Currently, the most promising macrophage ligand in clinical use is PK11195 which binds to peripheral benzodiazepine receptors in mitochondrial membranes, particularly in macrophages.39 Studies are currently under way to evaluate the potential of this ligand to image atherosclerosis using PET.
Synthesis, Enzyme Localization, and Regulation of Neurosteroids
Published in Sheryl S. Smith, Neurosteroid Effects in the Central Nervous System, 2003
receptor, J. Med. Chem., 40, 2435-2439, 1997. File, S.E. and Pellow, S., The effects of PK 11195, a ligand for benzodiazepine binding sites, in animal tests of anxiety and stress, Pharmacol. Biochem. Behav., 23, 737-741,
A single dose of ketamine cannot prevent protracted stress-induced anhedonia and neuroinflammation in rats
Published in Stress, 2022
Rodrigo Moraga-Amaro, Cyprien G. J. Guerrin, Luiza Reali Nazario, Bruno Lima Giacobbo, Rudi A. J. O. Dierckx, Jimmy Stehberg, Erik F. J. de Vries, Janine Doorduin
Limitations of this study include the inability of [11C]-PK11195 to discriminate between a pro- and anti-inflammatory immune response. Consequently, it is not possible to determine if the increase in TSPO expression in the insular and entorhinal cortex are caused by a more anti-inflammatory or pro-inflammatory immune response. Assessment of circulating inflammatory cytokines and postmortem immunohistochemical analyses of the brains could provide this complementary information. Additionally, more studies using other dosing regimens and/or different evaluation time points after the ketamine injection could help in the exploration of the relationship between ketamine’s antidepressant effects and neuroinflammation. Moreover, in our study, only the SPT test for parameters associated with depressive-like behavior was included. The use of additional behavioral tests to assess different types of depressive-like behavior, such as learned helplessness, could improve translation of these results to the clinical situation.
Gadolinium-conjugated CB86: a novel TSPO-targeting MRI contrast agent for imaging of rheumatoid arthritis
Published in Journal of Drug Targeting, 2020
Zhenyu Hou, Qiang Wang, Zhide Guo, Tingting Wang, Huanhua Wu, Chao Ma, Weixing Wang, Fu Su, Huijuan Zhang, Xinhui Su
The translocator protein 18 kDa (TSPO) is a mitochondrial membrane protein that is up-regulated in activated macrophages [6,7]. It has been shown that TSPO plays a role in the modulation of macrophages in the inflamed area [6,7]. TSPO has been thus recognised as a suitable biomarker candidate for inflammatory diseases screening and therapy [8,9]. As a result, a large number of positron emission tomography (PET) imaging based TSPO radioligands can visualise RA, such as 11C-(R)- PK11195, 11C-DPA-713, and 18FDPA-714 [8,10,11]. PK11195 is a classic ligand of TSPO. Due to the low in vivo specific binding of 11C-PK11195, recent efforts have focussed on identifying novel compounds that selectively bind to TSPO with high affinity in an effort to improve the delineation of in vivo specific binding [12]. In this regard, many new classes of compounds have been identified to have members that bind TSPO specifically with low nanomolar or sub-nanomolar affinity. Among these novel compounds, CB86 has been shown higher affinity (IC50 = 1.6 nM) compared to PK11195 (IC50 = 2.2 nM) [13].
GABA(A) receptor-targeted drug development -New perspectives in perioperative anesthesia
Published in Expert Opinion on Drug Discovery, 2019
Bernd Antkowiak, Gerhard Rammes
The isoquinoline carboxamide PK 11195 is the most widely researched TSPO ligand for neurodegenerative diseases [212]. Moreover, numerous PK 11195 analogues (e.g., [11C]VC195 (2)) have been studied as radioligands for potential PET or SPECT imaging agents for glial activation or neuroinflammation [229]. Investigations of the contribution of TSPO-ligands to CNS neuroprotection have been limited mostly to the classical ligands Ro5-4864 and PK-11195. However, their usefulness is limited in vivo owing to their low solubility, low brain uptake and inconsistent effects. Moreover, PK-11195 displays agonistic or antagonistic effects depending on the cell type and tissue environment and/or on the presence of an endogenous ligand [230].