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

Abstract

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 [(11)C]CLINME were studied in a rat model of local acute neuroinflammation, and compared with the reference compound [(11)C]PK11195, using autoradiography and PET imaging. Immunohistochemistry study was performed to validate the imaging data. [(11)C]CLINME exhibited a higher contrast between the PBR-expressing lesion site and the intact side of the same rat brain than [(11)C]PK11195 (2.14 +/- 0.09 vs. 1.62 +/- 0.05 fold increase, respectively). The difference was due to a lower uptake for [(11)C]CLINME than for [(11)C]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 R(1) was similar for both ligands (R(1) approximately 1), with [(11)C]CLINME exhibiting a higher binding potential than [(11)C]PK11195 (1.07 +/- 0.30 vs. 0.66 +/- 0.15). The results show that [(11)C]CLINME performs better than [(11)C]PK11195 in this model. Further studies of this new compound should be carried out to better define its capacity to overcome the limitations of [(11)C]PK11195 for PBR PET imaging.

Comparative Evaluation of the Translocator Protein Radioligands 11C-DPA-713, 18F-DPA-714, and 11C-PK11195 in a Rat Model of Acute Neuroinflammation

“…Recently, 18 18 F-labeled derivative, demonstrated TSPO specificity and interesting biodistribution properties in primates (12). In the present paper, we report in vitro autoradiography and in vivo PET of 18 F-DPA-714 in comparison to 11 C-PK11195 and 11 C-DPA-713 ( Fig.…”

Detection of Microglial Activation in an Acute Model of Neuroinflammation Using PET and Radiotracers11C-(R)-PK11195 and18F-GE-180

“…The intrastriatal injection of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic has been used in several studies (24)(25)(26) and was used primarily to study the effect of excitotoxity on glial activation (27). The pathology is associated with considerable cell death (28), which could be considered a confound, and maximal activation of the microglia and astrocytes occurs after 7 d (26).…”

Assessment of Neuroinflammation in Transferred EAE Via a Translocator Protein Ligand

“…Although [ 11 C]-(R)-PK11195 is widely used for imaging of microglia, its considerable high plasma protein binding, high levels of nonspecific binding, relatively poor blood-brain barrier permeability and short half-life, limits its use in brain imaging (Chauveau et al, 2008). Recently, alternative PET radioligands for TSPO including the phenoxyarylacetamide derivative [ 11 C]-DAA1106 and its analogues (Gulyas et al, 2009;Takano et al, 2010;Venneti et al, 2008), the imidazopyridines (PBR111) and its analogues (Boutin et al, 2007a;Fookes et al, 2008) (Boutin et al, 2007b;James et al, 2008) have been investigated.…”