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

Tiwari AK, Ji B, Yui J, Fujinaga M, Yamasaki T, Xie L, Luo R, Shimoda Y, Kumata K, Zhang Y, Hatori A, Maeda J, Higuchi M, Wang F, Zhang MR - Theranostics (2015)

Bottom Line: 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.In vitro autoradiography on postmortem human brains showed that TSPO rs6971 polymorphism did not affect binding sites for [(18)F]FEBMP.These findings suggest that [(18)F]FEBMP is a promising new tool for visualization of neuroinflammation.

View Article: PubMed Central - PubMed

Affiliation: 1. Molecular Imaging Centre, National Institute of Radiological Sciences, Chiba, Japan ; 2. Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India.

ABSTRACT
We evaluated the efficacy of 2-[5-(4-[(18)F]fluoroethoxy-2-oxo-1,3-benzoxazol-3(2H)-yl)-N-methyl-N-phenylacetamide] ([(18)F]FEBMP) for positron emission tomography (PET) imaging of translocator protein (18 kDa, TSPO). Dissection was used to determine the distribution of [(18)F]FEBMP in mice, while small-animal PET and metabolite analysis were used for a rat model of focal cerebral ischemia. [(18)F]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 [(18)F]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 [(18)F]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 [(18)F]FEBMP. These findings suggest that [(18)F]FEBMP is a promising new tool for visualization of neuroinflammation.

No MeSH data available.


Related in: MedlinePlus

Chemical structure of novel TSPO ligands
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Figure 1: Chemical structure of novel TSPO ligands

Mentions: Therefore, new TSPO ligand candidates with different structural skeletons that are not sensitive to this polymorphism are desirable. Recently, we developed 2-[5-(4-[11C]methoxyphenyl)-2-oxo-1,3-benzoxazol-3(2H)-yl]-N-methyl-N-phenylacetamide ([11C]MBMP, Fig. 1) as a potent and selective PET ligand for TSPO 22. An in vivo PET study demonstrated high specific binding and a higher binding potential of [11C]MBMP than (R)[11C]PK11195 toward TSPO in the ischemic rat brain. Because 18F has a longer half-life than 11C, we altered the methoxy group using a fluoroethoxy group to derive 2-[5-(4-fluoroethoxy-2-oxo-1,3-benzoxazol-3(2H)-yl)-N-methyl-N-phenylacetamide (FEBMP, Fig. 1). Importantly, this replacement did not change the binding affinity (Ki) of the molecule for TSPO in a decisive way (MBMP vs FEBMP: 3.9 ± 0.6 nM vs. 6.6 ± 0.7 nM) 23.


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

Tiwari AK, Ji B, Yui J, Fujinaga M, Yamasaki T, Xie L, Luo R, Shimoda Y, Kumata K, Zhang Y, Hatori A, Maeda J, Higuchi M, Wang F, Zhang MR - Theranostics (2015)

Chemical structure of novel TSPO ligands
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4493534&req=5

Figure 1: Chemical structure of novel TSPO ligands
Mentions: Therefore, new TSPO ligand candidates with different structural skeletons that are not sensitive to this polymorphism are desirable. Recently, we developed 2-[5-(4-[11C]methoxyphenyl)-2-oxo-1,3-benzoxazol-3(2H)-yl]-N-methyl-N-phenylacetamide ([11C]MBMP, Fig. 1) as a potent and selective PET ligand for TSPO 22. An in vivo PET study demonstrated high specific binding and a higher binding potential of [11C]MBMP than (R)[11C]PK11195 toward TSPO in the ischemic rat brain. Because 18F has a longer half-life than 11C, we altered the methoxy group using a fluoroethoxy group to derive 2-[5-(4-fluoroethoxy-2-oxo-1,3-benzoxazol-3(2H)-yl)-N-methyl-N-phenylacetamide (FEBMP, Fig. 1). Importantly, this replacement did not change the binding affinity (Ki) of the molecule for TSPO in a decisive way (MBMP vs FEBMP: 3.9 ± 0.6 nM vs. 6.6 ± 0.7 nM) 23.

Bottom Line: 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.In vitro autoradiography on postmortem human brains showed that TSPO rs6971 polymorphism did not affect binding sites for [(18)F]FEBMP.These findings suggest that [(18)F]FEBMP is a promising new tool for visualization of neuroinflammation.

View Article: PubMed Central - PubMed

Affiliation: 1. Molecular Imaging Centre, National Institute of Radiological Sciences, Chiba, Japan ; 2. Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India.

ABSTRACT
We evaluated the efficacy of 2-[5-(4-[(18)F]fluoroethoxy-2-oxo-1,3-benzoxazol-3(2H)-yl)-N-methyl-N-phenylacetamide] ([(18)F]FEBMP) for positron emission tomography (PET) imaging of translocator protein (18 kDa, TSPO). Dissection was used to determine the distribution of [(18)F]FEBMP in mice, while small-animal PET and metabolite analysis were used for a rat model of focal cerebral ischemia. [(18)F]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 [(18)F]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 [(18)F]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 [(18)F]FEBMP. These findings suggest that [(18)F]FEBMP is a promising new tool for visualization of neuroinflammation.

No MeSH data available.


Related in: MedlinePlus