[¹⁸F]FEBMP: Positron Emission Tomography Imaging of TSPO in a Model of Neuroinflammation in Rats, and in vitro Autoradiograms of the Human Brain

Abstract

We evaluated the efficacy of 2-[5-(4-[18F]fluoroethoxy-2-oxo-1,3-benzoxazol-3(2H)-yl)-N-methyl-N-phenylacetamide] ([18F]FEBMP) for positron emission tomography (PET) imaging of translocator protein (18 kDa, TSPO). Dissection was used to determine the distribution of [18F]FEBMP in mice, while small-animal PET and metabolite analysis were used for a rat model of focal cerebral ischemia. [18F]FEBMP showed high radioactivity uptake in mouse peripheral organs enriched with TSPO, and relatively high initial brain uptake (2.67 ± 0.12% ID/g). PET imaging revealed an increased accumulation of radioactivity in the infarcted striatum, with a maximum ratio of 3.20 ± 0.12, compared to non-injured striatum. Displacement with specific TSPO ligands lowered the accumulation levels in infarcts to those on the contralateral side. This suggests that the increased accumulation reflected TPSO-specific binding of [18F]FEBMP in vivo. Using a simplified reference tissue model, the binding potential on the infarcted area was 2.72 ± 0.27. Metabolite analysis in brain tissues showed that 83.2 ± 7.4% and 76.4 ± 2.1% of radioactivity was from intact [18F]FEBMP at 30 and 60 min, respectively, and that this ratio was higher than in plasma (8.6 ± 1.9% and 3.9 ± 1.1%, respectively). In vitro autoradiography on postmortem human brains showed that TSPO rs6971 polymorphism did not affect binding sites for [18F]FEBMP. These findings suggest that [18F]FEBMP is a promising new tool for visualization of neuroinflammation.

Modified benzoxazolone derivative as 18‐kDa TSPO ligand

“…The similar trend was observed at site 2 of the Ala147Thr AP‐TSPO mutant with the slight decrease in the binding score due to the presence of either no interactions or only hydrogen bonding or π–π stacking with Trp93 in all the ligands. This has been also confirmed in our experimental studies for PK11195 and MBMP analogues …”

“…In our previous studies post‐mortem human brains (two HABs and two LABs) were used for in vitro autoradiographic studies for a correlation analysis . Autoradiography with known ligands [ 11 C]AC‐5216 and [ 11 C]DAA1106 showed decreased binding in LAB‐1 compared to ( R )[ 11 C]PK11195, and this is also consistent with previous publications.…”

“…Moreover, there was an excellent correlation ( R = 0.98, p < .01) between the ratio of binding of TSPO ligands for HAB‐1 to LAB‐1 (R B(L/H) ). The presence of unlabelled PK11195 caused a significant decrease in the binding of [ 18 F]FEBMP in both human brains, and the R Ki(L/H) value of [ 18 F]FEBMP was estimated to be 0.9, suggesting that binding of MBMP and their derivatives have very little affect by TSPO rs6971 polymorphism …”

“…Therefore, a new candidate as TSPO ligand with different structural skeleton is desirable. Recently, we have synthesized a new series of PET ligands 2‐[5‐(4‐methoxyphenyl)‐ 2‐oxo‐1,3‐benzoxazol‐3( 2H )‐yl]‐ N ‐methyl‐ N ‐phenyl acetamide labelled with carbon‐11 ([ 11 C]MBMP) and two new 18F‐labelled molecules, 2‐[5‐(4‐[ 18 F]fluoroethoxy‐ ([ 18 F]FEBMP) and 2‐[5‐(4‐[ 18 F]fluoropropyloxy‐ ([ 18 F]FPBMP) ‐2‐oxo‐1,3‐benzoxazol‐3( 2H )‐yl)‐ N ‐methyl‐ N ‐phenyl acetamide (Figure ) and evaluated in vitro and in vivo for imaging of TSPO expression in brain . The in vitro autoradiography and in vivo PET study demonstrated appropriate specific binding and higher binding potential of [ 11 C]MBMP toward TSPO in the ischemic rat brain but moderate kinetics in primates (unpublished data).…”

Assessment of safety, efficacy, and dosimetry of a novel 18-kDa translocator protein ligand, [11C]CB184, in healthy human volunteers

“…To clarify these points, future studies should be performed to determine whether significant differences are present in [ 11 C]CB184 binding among different types of rs6971 polymorphisms. For this purpose, in vitro autoradiographic analyses in postmortem human brain [31] will be effective to prove the influence of rs6971 polymorphisms on the binding affinity of CB184.…”