In vivo Imaging of brain lesions with [C-11]CLINME, a new PET radioligand of peripheral benzodiazepine receptors

Faculty of Life Sciences, University of Manchester, United Kingdom
Glia (Impact Factor: 6.03). 11/2007; 55(14):1459 - 1468. DOI: 10.1002/glia.20562


The peripheral benzodiazepine receptor (PBR) is expressed by microglial cells in many neuropathologies involving neuroinflammation. PK11195, the reference compound for PBR, is used for positron emission tomography (PET) imaging but has a limited capacity to quantify PBR expression. Here we describe the new PBR ligand CLINME as an alternative to PK11195. In vitro and in vivo imaging properties of [11C]CLINME were studied in a rat model of local acute neuroinflammation, and compared with the reference compound [11C]PK11195, using autoradiography and PET imaging. Immunohistochemistry study was performed to validate the imaging data. [11C]CLINME exhibited a higher contrast between the PBR-expressing lesion site and the intact side of the same rat brain than [11C]PK11195 (2.14 ± 0.09 vs. 1.62 ± 0.05 fold increase, respectively). The difference was due to a lower uptake for [11C]CLINME than for [11C]PK11195 in the non-inflammatory part of the brain in which PBR was not expressed, while uptake levels in the lesion were similar for both tracers. Tracer localization correlated well with that of activated microglial cells, demonstrated by immunohistochemistry and PBR expression detected by autoradiography. Modeling using the simplified tissue reference model showed that R1 was similar for both ligands (R1 ∼ 1), with [11C]CLINME exhibiting a higher binding potential than [11C]PK11195 (1.07 ± 0.30 vs. 0.66 ± 0.15). The results show that [11C]CLINME performs better than [11C]PK11195 in this model. Further studies of this new compound should be carried out to better define its capacity to overcome the limitations of [11C]PK11195 for PBR PET imaging. © 2007 Wiley-Liss, Inc.

Download full-text


Available from: Herve Boutin, Jul 14, 2014
  • Source
    • "probes designed for binding to inflammatory processes, such as [ 11 C]PK11195, [ 11 C]DAA1106, [ 11 C]DPA-713, and [ 11 C]CLINME have been widely used for studying brain infl ammation [60] [61] [62] [63] . The principal immune cells in the central nervous system, microglia, are activated in response to inflammatory processes in the brain [64] . "
    [Show abstract] [Hide abstract]
    ABSTRACT: A migraine is a recurring neurological disorder characterized by unilateral, intense, and pulsatile headaches. In one-third of migraine patients, the attacks are preceded by a visual aura, such as a slowly-propagating scintillating scotoma. Migraine aura is thought to be a result of the neurovascular phenomenon of cortical spreading depression (SD), a self-propagating wave of depolarization that spreads across the cerebral cortex. Several animal experiments have demonstrated that cortical SD causes intracranial neurogenic inflammation around the meningeal blood vessels, such as plasma protein extravasation and pro-inflammatory peptide release. Cortical SD has also been reported to activate both peripheral and central trigeminal nociceptive pathways. Although several issues remain to be resolved, recent evidence suggests that cortical SD could be the initial trigger of intracranial neurogenic inflammation, which then contributes to migraine headaches via subsequent activation of trigeminal afferents.
    Full-text · Article · Oct 2014 · Neuroscience Bulletin
  • Source
    • "They have been used to explore TSPO distribution and function in various tissues and pathologies becoming useful in mapping the " peripheral binding site " in almost every tissue examined. More recently, new structurally diverse TSPO drug ligands have been developed and used for functional and imaging studies such as 2-phenylindole-3-acetamides (e.g., FGIN-1) [22], phenoxyarylacetamides (e.g., DAA1106) [23] [24], imidazo[1,2-a] pyridines (e.g., CLINME) [23] [25], and pyrazolopyrimidines (e.g., DPA- 713) [23] [24]. To our knowledge, none of all the above cited TSPO drug ligands contain organic functions such as amino-, hydroxy-and carboxylic-groups potentially useful for their further conjugation with diagnostic-or with nanovector-imaging agents. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondria represents an attractive subcellular target due to its function particularly important for oxidative damage, calcium metabolism and apoptosis. However, the concept of mitochondrial targeting has been a neglected area so far. The translocator protein (TSPO), represents an interesting subcellular target not only to image disease states overexpressing this protein, but also for a selective mitochondrial drug targeting. Recently, we have delivered in vitro and in vivo small molecule imaging agents into cells overexpressing TSPO by using a family of high-affinity conjugable ligands characterized by 2-phenyl-imidazo[1,2-a]pyridine acetamide structure. As an extension, in the present work we studied the possibility to target and image TSPO with dendrimers. These nano-platforms have unique features, in fact, are prepared with a level of control not reachable with most linear polymers, leading to nearly monodisperse, globular macromolecules with a large number of peripheral groups. As a consequence, they are an ideal delivery vehicle candidate for explicit study of the effects of polymer size, charge, composition, and architecture on biologically relevant properties such as lipid bilayer interactions, cytotoxicity, cellular internalization, and subcellular compartments and organelles interactions. Here, we present the synthesis, characterization, cellular internalization, and mitochondria labeling of a TSPO targeted fourth generation [G(4)-PAMAM] dendrimer nanoparticle labeled with the organic fluorescent dye fluorescein. We comprehensively studied the cellular uptake behavior of these dendrimers, into glioma C6 cell line, under the influence of various endocytosis inhibitors. We found that TSPO targeted-G(4)-PAMAM-FITC dendrimer is quickly taken up by these cells by endocytosis pathways, and moreover specifically targets the mitochondria as evidenced from subcellular fractionation experiments and co-localization studies performed with CAT (Confocal-AFM-TIRF) microscopy.
    Full-text · Article · Oct 2013 · Journal of Controlled Release
  • Source
    • "Numerous radiolabeled TSPO ligands have been developed and evaluated in animal models of disease and in humans; of these [11C]PK11195 is the ligand most extensively studied [10], [11]. Several other ligands with improved properties (e.g. higher affinity, lower lipophilicity) have been described including [11C]vinpocetin [12], [18F]FMDAA1106, [18F]FEDAA1106 [13], [123I]CLINDE [14], [11C]CLINME [15], [18F]FEPPA or [18F]PBR28 [16], [11C]DAC [17], and [11C]DAA1106 [18]. The pyrazolopyrimidine [18F]DPA-714 was introduced in 2008 by James and colleagues as a highly specific new radioligand for TSPO with improved imaging properties over [11C]PK11195 [19]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Inflammation is a pathophysiological hallmark of many diseases of the brain. Specific imaging of cells and molecules that contribute to cerebral inflammation is therefore highly desirable, both for research and in clinical application. The 18 kDa translocator protein (TSPO) has been established as a suitable target for the detection of activated microglia/macrophages. A number of novel TSPO ligands have been developed recently. Here, we evaluated the high affinity TSPO ligand DPA-714 as a marker of brain inflammation in two independent animal models. For the first time, the specificity of radiolabeled DPA-714 for activated microglia/macrophages was studied in a rat model of epilepsy (induced using Kainic acid) and in a mouse model of stroke (transient middle cerebral artery occlusion, tMCAO) using high-resolution autoradiography and immunohistochemistry. Additionally, cold-compound blocking experiments were performed and changes in blood-brain barrier (BBB) permeability were determined. Target-to-background ratios of 2 and 3 were achieved in lesioned vs. unaffected brain tissue in the epilepsy and tMCAO models, respectively. In both models, ligand uptake into the lesion corresponded well with the extent of Ox42- or Iba1-immunoreactive activated microglia/macrophages. In the epilepsy model, ligand uptake was almost completely blocked by pre-injection of DPA-714 and FEDAA1106, another high-affinity TSPO ligand. Ligand uptake was independent of the degree of BBB opening and lesion size in the stroke model. We provide further strong evidence that DPA-714 is a specific ligand to image activated microglia/macrophages in experimental models of brain inflammation.
    Full-text · Article · Aug 2013 · PLoS ONE
Show more