Radiosynthesis,In VivoBiological Evaluation, and Imaging of Brain Lesions with [¹²³I]-CLINME, a New SPECT Tracer for the Translocator Protein

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.

Modified benzoxazolone (ABO‐AA) based single photon emission computed tomography (SPECT) probes for 18 kDa translocator protein

“…Comparison of release rate among SPECT agents between 30 and 60 min for 99m Tc-MBIP-Cl, [ 123 I]-CLINME (Mattner et al, 2015), 99m Tclabeled 2-quinolinecarboxamide and 99m Tc-MBIP-Br reflected better release rate of 99m Tc-MBIP-Cl in lung, liver, heart, and spleen (Cappelli et al, 2008;Srivastava et al, 2016). Further, it was also compared with PET and SPECT ligands of ABO category.…”

“…Translocator protein (TSPO) first described as peripheral benzodiazepine receptor (PBR) is a 18 kDa protein and initially identified in 1977 as peripheral binding site for the benzodiazepine. The name PBR described its high affinity binding to benzodiazepine in peripheral tissues (Chen & Guilarte, 2008;Fan, Lindemann, Feuilloley, & Papadopoulos, 2012;Milenkovic, Rupprecht, & Wetzel, 2015;Veenman, Vainshtein, & Gavish, 2015). It is an intracellular protein which forms a complex with voltage dependent anion channel (VCAD, 32 kDa) and adenine nucleotide translocator (ANT, 30 kDa) in mitochondria.…”

The 18-kDa Translocator Protein PET Tracers as a Diagnostic Marker for Neuroinflammation: Development and Current Standing

“… 100 It is also radiolabeled with the 123-I isotope (with 70–80% radiochemical yield) by the electrophilic introduction of a tributyltin precursor using 123 / 125 I-sodium iodide in acetic acid and per acetic acid as the oxidant. 101 It showed high binding for TSPO, but under in vivo conditions the uptake was lower in the noninflammatory brain region compared to [ 11 C]PK11195, but in inflammation regions both tracers display almost similar uptakes. 100 [ 11 C]CLINME is perceived as superior tracer among imidazopyridine tracers as it displays almost 100-fold higher specificity for TSPO against CBR.…”

“…This skeleton has been used for PET imaging with radiolabeling with either I-123 or C-11 and 99 mTc based SPECT imaging. 101 , 102 …”

“…CLINME is (2-[6-chloro-2-(4-iodophenyl)-imidazo­[1,2- a ]­pyridin-3-yl]-N-ethyl-acetamide), which is radiolabeled with C-11 . It is also radiolabeled with the 123-I isotope (with 70–80% radiochemical yield) by the electrophilic introduction of a tributyltin precursor using 123 / 125 I-sodium iodide in acetic acid and per acetic acid as the oxidant . It showed high binding for TSPO, but under in vivo conditions the uptake was lower in the noninflammatory brain region compared to [ 11 C]­PK11195, but in inflammation regions both tracers display almost similar uptakes .…”