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FIBT versus florbetaben and PiB: a preclinical comparison study with amyloid-PET in transgenic mice.

Yousefi BH, von Reutern B, Scherübl D, Manook A, Schwaiger M, Grimmer T, Henriksen G, Förster S, Drzezga A, Wester HJ - EJNMMI Res (2015)

Bottom Line: However, distinct study cohorts and different quantification techniques allow only for an indirect comparison between the different tracers.The SUVRs in transgenic versus control animals (SUVRtg/SUVRctl) for FIBT (1.78 ± 0.16) were similar to the ratios as observed in humans (SUVRAD/SUVRctl) for the established gold standard Pittsburgh compound B (PiB) (1.65 ± 0.41).Moreover, the preclinical study design is recommendable for reliable assessment and comparison of novel radiopharmaceuticals.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Radiochemistry, Technische Universität München, Walther-Meißner-Str. 3, 85748 Garching, Germany.

ABSTRACT

Background: Over the last decade, an increasing number of studies have been published on the use of amyloid-β (Aβ) PET imaging with different (18)F-radiopharmaceuticals for clinical characterization of Alzheimer's disease (AD) in different stages. However, distinct study cohorts and different quantification techniques allow only for an indirect comparison between the different tracers. Thus, the aim of this study was the direct intra-individual in vivo comparison of different Aβ-targeted radiopharmaceuticals for PET imaging, including the newly developed agent [(18)F]FIBT.

Methods: A small group of four animals of a well-characterized APP/PS1 transgenic (tg) mouse model of AD and gender-matched control (ctl) animals underwent a sequential and standardized PET imaging regimen for direct comparison of [(18)F]FIBT, [(18)F]florbetaben, and [(11)C]PiB. The quantitative PET imaging data were cross-validated with the cerebral Aβ plaque load as quantified ex vivo on histological sections.

Results: We found that FIBT (2-(p-methylaminophenyl)-7-(2-[(18)F]fluoroethoxy)imidazo[2,1-b]benzothiazole) compares favorably to florbetaben as a high-contrasting PET radiopharmaceutical for imaging Aβ pathology. The excellent pharmacokinetics of FIBT in combination with its high-binding affinity towards Aβ resulted in feasible high-contrast imaging of Aβ with high global cortex to cerebellum standard uptake value ratio (SUVR) in 24-month-old tg mice (tg 1.68 ± 0.15 vs. ctl 0.95 ± 0.02). The SUVRs in transgenic versus control animals (SUVRtg/SUVRctl) for FIBT (1.78 ± 0.16) were similar to the ratios as observed in humans (SUVRAD/SUVRctl) for the established gold standard Pittsburgh compound B (PiB) (1.65 ± 0.41).

Conclusions: This head-to-head PET tracer comparison study in mice indicated the good imaging properties of [(18)F]FIBT, such as high initial brain uptake, fast clearance of the brain, and high binding affinity towards Aβ as directly compared to the established amyloid tracers. Moreover, the preclinical study design is recommendable for reliable assessment and comparison of novel radiopharmaceuticals.

No MeSH data available.


Related in: MedlinePlus

PET ratios and group-wise mean dynamic PET ratio. (A1) PET ratios within the same transgenic animals for FIBT (x-axis) and florbetaben (y-axis). (A2) Group-wise mean dynamic PET ratio curves for the three radiopharmaceuticals. The four different symbols in A1 mark the individual transgenic animal for which representative Thioflavin S staining images, and plaque load results are given in (B1) to (B4). White arrows point at artefacts in the cerebellum that do not represent amyloid plaques.
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Fig4: PET ratios and group-wise mean dynamic PET ratio. (A1) PET ratios within the same transgenic animals for FIBT (x-axis) and florbetaben (y-axis). (A2) Group-wise mean dynamic PET ratio curves for the three radiopharmaceuticals. The four different symbols in A1 mark the individual transgenic animal for which representative Thioflavin S staining images, and plaque load results are given in (B1) to (B4). White arrows point at artefacts in the cerebellum that do not represent amyloid plaques.

Mentions: In vivo small animal PET imaging of the three tracers was compared using a group of four APP/PS1 tg and three ctl mice, co-registered to the MRI template showing axial, sagittal, and coronal views of group-wise mean images (Figure 2). Dynamic PET time activity curves of the cortex-VOI and the cerebellum-VOI for FIBT, florbetaben, and PiB within identical mice are illustrated in Figure 3. The dynamic PET ratio curves are given in Figure 4, where tg and ctl mice showed significant differences in PET. [11C]PiB showed slightly lower initial uptake values than both 18F-tracers but considerably different wash-out. More pronounced [11C]PiB washout-out from Aβ-free regions was resulting in the highest target-to-reference-region ratios. The lower washout of [18F]florbetaben observed in BALB/c mice (Figure 1) was also observed on visual inspection of mean PET images of the control group. Here, a higher tracer retention of [18F]florbetaben compared to [18F]FIBT was detected in the brainstem (see red arrow in Figure 2). Furthermore, mean PET ratios (SUVR, calculated for time interval 36 to 45 min) for the APP/PS1 tg group and the control group as well as their ratio SUVRtg/SUVRctl are given in Table 3. Among the three tracers, [11C]PiB showed significantly higher unspecific nasal uptake in all cases. As observed for many PET tracers, all three tracers showed nonspecific uptake in the retrobulbar space, likely representing the Harderian gland.Figure 2


FIBT versus florbetaben and PiB: a preclinical comparison study with amyloid-PET in transgenic mice.

Yousefi BH, von Reutern B, Scherübl D, Manook A, Schwaiger M, Grimmer T, Henriksen G, Förster S, Drzezga A, Wester HJ - EJNMMI Res (2015)

PET ratios and group-wise mean dynamic PET ratio. (A1) PET ratios within the same transgenic animals for FIBT (x-axis) and florbetaben (y-axis). (A2) Group-wise mean dynamic PET ratio curves for the three radiopharmaceuticals. The four different symbols in A1 mark the individual transgenic animal for which representative Thioflavin S staining images, and plaque load results are given in (B1) to (B4). White arrows point at artefacts in the cerebellum that do not represent amyloid plaques.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4402683&req=5

Fig4: PET ratios and group-wise mean dynamic PET ratio. (A1) PET ratios within the same transgenic animals for FIBT (x-axis) and florbetaben (y-axis). (A2) Group-wise mean dynamic PET ratio curves for the three radiopharmaceuticals. The four different symbols in A1 mark the individual transgenic animal for which representative Thioflavin S staining images, and plaque load results are given in (B1) to (B4). White arrows point at artefacts in the cerebellum that do not represent amyloid plaques.
Mentions: In vivo small animal PET imaging of the three tracers was compared using a group of four APP/PS1 tg and three ctl mice, co-registered to the MRI template showing axial, sagittal, and coronal views of group-wise mean images (Figure 2). Dynamic PET time activity curves of the cortex-VOI and the cerebellum-VOI for FIBT, florbetaben, and PiB within identical mice are illustrated in Figure 3. The dynamic PET ratio curves are given in Figure 4, where tg and ctl mice showed significant differences in PET. [11C]PiB showed slightly lower initial uptake values than both 18F-tracers but considerably different wash-out. More pronounced [11C]PiB washout-out from Aβ-free regions was resulting in the highest target-to-reference-region ratios. The lower washout of [18F]florbetaben observed in BALB/c mice (Figure 1) was also observed on visual inspection of mean PET images of the control group. Here, a higher tracer retention of [18F]florbetaben compared to [18F]FIBT was detected in the brainstem (see red arrow in Figure 2). Furthermore, mean PET ratios (SUVR, calculated for time interval 36 to 45 min) for the APP/PS1 tg group and the control group as well as their ratio SUVRtg/SUVRctl are given in Table 3. Among the three tracers, [11C]PiB showed significantly higher unspecific nasal uptake in all cases. As observed for many PET tracers, all three tracers showed nonspecific uptake in the retrobulbar space, likely representing the Harderian gland.Figure 2

Bottom Line: However, distinct study cohorts and different quantification techniques allow only for an indirect comparison between the different tracers.The SUVRs in transgenic versus control animals (SUVRtg/SUVRctl) for FIBT (1.78 ± 0.16) were similar to the ratios as observed in humans (SUVRAD/SUVRctl) for the established gold standard Pittsburgh compound B (PiB) (1.65 ± 0.41).Moreover, the preclinical study design is recommendable for reliable assessment and comparison of novel radiopharmaceuticals.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Radiochemistry, Technische Universität München, Walther-Meißner-Str. 3, 85748 Garching, Germany.

ABSTRACT

Background: Over the last decade, an increasing number of studies have been published on the use of amyloid-β (Aβ) PET imaging with different (18)F-radiopharmaceuticals for clinical characterization of Alzheimer's disease (AD) in different stages. However, distinct study cohorts and different quantification techniques allow only for an indirect comparison between the different tracers. Thus, the aim of this study was the direct intra-individual in vivo comparison of different Aβ-targeted radiopharmaceuticals for PET imaging, including the newly developed agent [(18)F]FIBT.

Methods: A small group of four animals of a well-characterized APP/PS1 transgenic (tg) mouse model of AD and gender-matched control (ctl) animals underwent a sequential and standardized PET imaging regimen for direct comparison of [(18)F]FIBT, [(18)F]florbetaben, and [(11)C]PiB. The quantitative PET imaging data were cross-validated with the cerebral Aβ plaque load as quantified ex vivo on histological sections.

Results: We found that FIBT (2-(p-methylaminophenyl)-7-(2-[(18)F]fluoroethoxy)imidazo[2,1-b]benzothiazole) compares favorably to florbetaben as a high-contrasting PET radiopharmaceutical for imaging Aβ pathology. The excellent pharmacokinetics of FIBT in combination with its high-binding affinity towards Aβ resulted in feasible high-contrast imaging of Aβ with high global cortex to cerebellum standard uptake value ratio (SUVR) in 24-month-old tg mice (tg 1.68 ± 0.15 vs. ctl 0.95 ± 0.02). The SUVRs in transgenic versus control animals (SUVRtg/SUVRctl) for FIBT (1.78 ± 0.16) were similar to the ratios as observed in humans (SUVRAD/SUVRctl) for the established gold standard Pittsburgh compound B (PiB) (1.65 ± 0.41).

Conclusions: This head-to-head PET tracer comparison study in mice indicated the good imaging properties of [(18)F]FIBT, such as high initial brain uptake, fast clearance of the brain, and high binding affinity towards Aβ as directly compared to the established amyloid tracers. Moreover, the preclinical study design is recommendable for reliable assessment and comparison of novel radiopharmaceuticals.

No MeSH data available.


Related in: MedlinePlus