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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

In vitro autoradiographic analysis of the human brain. (A) Autoradiographic images of (R)[11C]PK11195, [11C]PBR28, [11C]AC-5216, and [11C]DAA1106 in brain sections containing the temporal cortex from LAB-1 and HAB-1. The binding ratios of (R)[11C]PK11195, [11C]DAA1106, [11C]AC-5216 and [11C]PBR28 for HAB-1 to that of LAB-1 (RB(H/L)) were approximately 0.45, 1.19, 4.60, and 11.1, respectively, showing excellent correlation (R = 0.98, p < 0.01) with the Ki ratios of these ligands for LAB to that of HAB (RKi(H/L)). The corresponding values of RKi(H/L) of these lignads were 0.8, 4.7, 12.6 and 55, respectively, published in previous studies (Owen et al, 2011a, 2011b). (B) Autoradiographic images of [18F]FEBMP and quantitative analysis. Total binding (TB, PSL/mm2; mean ± SEM) and non-specific binding (NSB, PSL/mm2; mean ± SEM) were calculated in the absence and presence of unlabeled PK11195, respectively (3 and 5 brain sections for the NSB and TB assay, respectively; *, p < 0.05, **, p < 0.01; student's t-test for TB vs NSB). The RB(L/H) value of [18F]FEBMP was determined to be 0.90 from the bar graph. *The RKi(L/H) value (0.9) of [18F]FEBMP was calculated by extrapolation from the linear curve (A) and RB(L/H) value.
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Figure 4: In vitro autoradiographic analysis of the human brain. (A) Autoradiographic images of (R)[11C]PK11195, [11C]PBR28, [11C]AC-5216, and [11C]DAA1106 in brain sections containing the temporal cortex from LAB-1 and HAB-1. The binding ratios of (R)[11C]PK11195, [11C]DAA1106, [11C]AC-5216 and [11C]PBR28 for HAB-1 to that of LAB-1 (RB(H/L)) were approximately 0.45, 1.19, 4.60, and 11.1, respectively, showing excellent correlation (R = 0.98, p < 0.01) with the Ki ratios of these ligands for LAB to that of HAB (RKi(H/L)). The corresponding values of RKi(H/L) of these lignads were 0.8, 4.7, 12.6 and 55, respectively, published in previous studies (Owen et al, 2011a, 2011b). (B) Autoradiographic images of [18F]FEBMP and quantitative analysis. Total binding (TB, PSL/mm2; mean ± SEM) and non-specific binding (NSB, PSL/mm2; mean ± SEM) were calculated in the absence and presence of unlabeled PK11195, respectively (3 and 5 brain sections for the NSB and TB assay, respectively; *, p < 0.05, **, p < 0.01; student's t-test for TB vs NSB). The RB(L/H) value of [18F]FEBMP was determined to be 0.90 from the bar graph. *The RKi(L/H) value (0.9) of [18F]FEBMP was calculated by extrapolation from the linear curve (A) and RB(L/H) value.

Mentions: Autoradiographic analyses with (R)[11C]PK11195, [11C]PBR28, [11C]AC-5216, and [11C]DAA1106 showed that there were overtly different binding sites for these radioligands between two postmortem human brains, LAB-1 and HAB-1 (Fig. 4). In vitro binding of (R)[11C]PK11195 was a little higher in LAB-1 than in HAB-1. On the other hand, compared to (R)[11C]PK11195, in vitro binding of [11C]PBR28 was greatly lower in LAB-1. The binding in LAB-1 was also lower than in HAB-1 (Fig. 4A).


[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)

In vitro autoradiographic analysis of the human brain. (A) Autoradiographic images of (R)[11C]PK11195, [11C]PBR28, [11C]AC-5216, and [11C]DAA1106 in brain sections containing the temporal cortex from LAB-1 and HAB-1. The binding ratios of (R)[11C]PK11195, [11C]DAA1106, [11C]AC-5216 and [11C]PBR28 for HAB-1 to that of LAB-1 (RB(H/L)) were approximately 0.45, 1.19, 4.60, and 11.1, respectively, showing excellent correlation (R = 0.98, p < 0.01) with the Ki ratios of these ligands for LAB to that of HAB (RKi(H/L)). The corresponding values of RKi(H/L) of these lignads were 0.8, 4.7, 12.6 and 55, respectively, published in previous studies (Owen et al, 2011a, 2011b). (B) Autoradiographic images of [18F]FEBMP and quantitative analysis. Total binding (TB, PSL/mm2; mean ± SEM) and non-specific binding (NSB, PSL/mm2; mean ± SEM) were calculated in the absence and presence of unlabeled PK11195, respectively (3 and 5 brain sections for the NSB and TB assay, respectively; *, p < 0.05, **, p < 0.01; student's t-test for TB vs NSB). The RB(L/H) value of [18F]FEBMP was determined to be 0.90 from the bar graph. *The RKi(L/H) value (0.9) of [18F]FEBMP was calculated by extrapolation from the linear curve (A) and RB(L/H) value.
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Related In: Results  -  Collection

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Figure 4: In vitro autoradiographic analysis of the human brain. (A) Autoradiographic images of (R)[11C]PK11195, [11C]PBR28, [11C]AC-5216, and [11C]DAA1106 in brain sections containing the temporal cortex from LAB-1 and HAB-1. The binding ratios of (R)[11C]PK11195, [11C]DAA1106, [11C]AC-5216 and [11C]PBR28 for HAB-1 to that of LAB-1 (RB(H/L)) were approximately 0.45, 1.19, 4.60, and 11.1, respectively, showing excellent correlation (R = 0.98, p < 0.01) with the Ki ratios of these ligands for LAB to that of HAB (RKi(H/L)). The corresponding values of RKi(H/L) of these lignads were 0.8, 4.7, 12.6 and 55, respectively, published in previous studies (Owen et al, 2011a, 2011b). (B) Autoradiographic images of [18F]FEBMP and quantitative analysis. Total binding (TB, PSL/mm2; mean ± SEM) and non-specific binding (NSB, PSL/mm2; mean ± SEM) were calculated in the absence and presence of unlabeled PK11195, respectively (3 and 5 brain sections for the NSB and TB assay, respectively; *, p < 0.05, **, p < 0.01; student's t-test for TB vs NSB). The RB(L/H) value of [18F]FEBMP was determined to be 0.90 from the bar graph. *The RKi(L/H) value (0.9) of [18F]FEBMP was calculated by extrapolation from the linear curve (A) and RB(L/H) value.
Mentions: Autoradiographic analyses with (R)[11C]PK11195, [11C]PBR28, [11C]AC-5216, and [11C]DAA1106 showed that there were overtly different binding sites for these radioligands between two postmortem human brains, LAB-1 and HAB-1 (Fig. 4). In vitro binding of (R)[11C]PK11195 was a little higher in LAB-1 than in HAB-1. On the other hand, compared to (R)[11C]PK11195, in vitro binding of [11C]PBR28 was greatly lower in LAB-1. The binding in LAB-1 was also lower than in HAB-1 (Fig. 4A).

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