Abstract
The high affinity translocator protein (TSPO) ligand 6-chloro-2-(4′-iodophenyl)-3-(N,N-methylethyl)imidazo[1,2-a]pyridine-3-acetamide (CLINME) was radiolabelled with iodine-123 and assessed for its sensitivity for the TSPO in rodents. Moreover neuroinflammatory changes on a unilateral excitotoxic lesion rat model were detected using SPECT imaging. [123I]-CLINME was prepared in 70–80% radiochemical yield. The uptake of [123I]-CLINME was evaluated in rats by biodistribution, competition, and metabolite studies. The unilateral excitotoxic lesion was performed by injection of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid unilaterally into the striatum. The striatum lesion was confirmed and correlated with TSPO expression in astrocytes and activated microglia by immunohistochemistry and autoradiography. In vivo studies with [123I]-CLINME indicated a biodistribution pattern consistent with TPSO distribution and the competition studies with PK11195 and Ro 5-4864 showed that [123I]-CLINME is selective for this site. The metabolite study showed that the extractable radioactivity was unchanged [123I]-CLINME in organs which expresses TSPO. SPECT/CT imaging on the unilateral excitotoxic lesion indicated that the mean ratio uptake in striatum (lesion : nonlesion) was 2.2. Moreover, TSPO changes observed by SPECT imaging were confirmed by immunofluorescence, immunochemistry, and autoradiography. These results indicated that [123I]-CLINME is a promising candidate for the quantification and visualization of TPSO expression in activated astroglia using SPECT.
Highlights
The 18 kDa translocator protein [1] (TSPO; previously known as the peripheral benzodiazepine receptor, PBR) has been extensively studied for its intricate biological functions
In vitro studies found that CLINME displayed a 110-fold higher selectivity for the TPSO over the central benzodiazepine receptor (CBR) compared to a 20fold difference to the related compounds, alpidem [38], and 200-fold for CLINDE [35]
In vivo the distribution of radioactivity after injection of [123I]-CLINME follows the distribution of the TPSO reported in the literature with high uptake in endocrine tissues, such as adrenal glands [39], in peripheral organs such as kidney and heart [17, 40] and low uptake in the brain [41, 42]
Summary
The 18 kDa translocator protein [1] (TSPO; previously known as the peripheral benzodiazepine receptor, PBR) has been extensively studied for its intricate biological functions. These compounds have been shown to localise in areas associated with microglia activation following a range of neurological insults [7] and a number of PET and SPECT clinical studies have been performed using [11C]-PK11195 [20,21,22] and [123I]-PK11195 [23] to detect microglia activation in humans These radiolabelled PK11195 analogues displayed a significant degree of nonspecific binding in vivo [24], a characteristic which can distort the imaging data. PK11195 and was better able to depict microglia activation following unilateral excitotoxic lesions in rodent models of inflammation than [11C]-PK11195 [31] As this molecule incorporates iodine, it presents an excellent opportunity to exploit additional studies when radiolabelled with iodine-125 for pharmacological studies as well as with iodine-123 and iodine-124 for use in SPECT and PET imaging, respectively. We report the radiolabelling, in vitro, in vivo pharmacological evaluation of the iodine-123 labelled analogue [123I]-CLINME and its in vivo imaging in a model of the unilateral excitotoxic lesion using SPECT
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