Current paradigm of the 18-kDa translocator protein (TSPO) as a molecular target for PET imaging in neuroinflammation and neurodegenerative diseases

Neuroinflammation is a process characterised by drastic changes in microglial morphology and by marked upregulation of the 18-kDa translocator protein (TSPO) on the mitochondria. The continual increase in incidence of neuroinflammation and neurodegenerative diseases poses a major health issue in many countries, requiring more innovative diagnostic and monitoring tools. TSPO expression may constitute a biomarker for brain inflammation that could be monitored by using TSPO tracers as neuroimaging agents. From medical imaging perspectives, this review focuses on the current concepts related to the TSPO, and discusses briefly on the status of its PET imaging related to neuroinflammation and neurodegenerative diseases in humans

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

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

Radiosynthesis of 2-[6-chloro-2-(4-iodophenyl)imidazo [1,2-a]pyridin-3-yl]-N-ethyl-N-[C-11]methyl-acetamide, [C-11]CLINME, a novel radioligand for imaging the peripheral benzodiazepine receptors with PET.

Recently, a new 2-(iodophenyl)imidazo[1,2-a]pyridineacetamide series has been developed as iodine-123-labelled radioligands for imaging the peripheral benzodiazepine receptors using single photon emission tomography. Within this series, 2-[6-chloro-2-(4-iodophenyl)-imidazo[1,2-alpyridin-3-yl]-N-ethyl-N-methyl-acetamide (CLINME) was considered as an appropriate candidate for positron emission tomography imaging and was isotopically labelled with carbon-11 (T-1/2: 20.38 min) at the methylacetamide side chain from the corresponding nor-analogue using [C-11]methyl iodide and the following experimental conditions: (1) trapping at -10 degrees C of [C-11]methyl iodide in a 1/2 (v:v) mixture of DMSO/DMF (300 mu l) containing 0.7-1.0 mg of the precursor for labelling and 3-5 mg of powdered potassium hydroxide (excess); (2) heating the reaction mixture at 110 degrees C for 3 min under a nitrogen stream; (3) diluting the residue with 0.6 ml of the HPLC mobile phase; and (4) purification using semi-preparative HPLC (Zorbax(R) SB18, Hewlett Packard, 250 x 9.4 mm). Typically, starting from a 1.5Ci (55.5 GBq) [C-11]CO2 production batch, 120-150 mCi (4.44-5.55 GBq) of [C-11]CLINME were obtained (16-23% decay-corrected radiochemical yield, n = 12) within a total synthesis time of 24-27 min (Sep-pak(R)Plus-based formulation included). Specific radio-activities ranged from 0.9 to 2.7 Ci/mu mol (33.3-99.9 GBq/mu mol) at the end of radiosynthesis. © 2007, Wiley-Blackwell. The definitive version is available at www3.interscience.wiley.co