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PET imaging of brain with the β-amyloid probe, [11C]6-OH-BTA-1, in a transgenic mouse model of Alzheimer’s disease

  • Molecular Imaging
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

The purpose of this study was to evaluate the capacity of [11C]6-OH-BTA-1 and positron emission tomography (PET) to quantify β-amyloid (Aβ) plaques in the Tg2576 mouse model of Alzheimer’s disease (AD).

Methods

PET imaging was performed with the NIH ATLAS small animal scanner in six elderly transgenic mice (Tg2576; age 22.0±1.8 months; 23.6±2.6 g) overexpressing a mutated form of human β-amyloid precursor protein (APP) known to result in the production of Aβ plaques, and in six elderly wild-type litter mates (age 21.8±1.6 months; 29.5±4.7 g). Dynamic PET scans were performed for 30 min in each mouse under 1% isoflurane inhalation anesthesia after a bolus injection of 13–46 MBq of [11C]6-OH-BTA-1. PET data were reconstructed with 3D OSEM. On the coronal PET image, irregular regions of interest (ROIs) were placed on frontal cortex (FR), parietal cortex (PA), striatum (ST), thalamus (TH), pons (PO), and cerebellum (CE), guided by a mouse stereotaxic atlas. Time–activity curves (TACs) (expressed as percent injected dose per gram normalized to body weight: % ID-kg/g) were obtained for FR, PA, ST, TH, PO, and CE. ROI-to-CE radioactivity ratios were also calculated. Following PET scans, sections of mouse brain prepared from anesthetized and fixative-perfused mice were stained with thioflavin-S.

Results

TACs for [11C]6-OH-BTA-1 in all ROIs peaked early (at 30–55 s), with radioactivity washing out quickly thereafter in both transgenic and wild-type mice. Peak uptake in all regions was significantly lower in transgenic mice than in wild-type mice. During the later part of the washout phase (12–30 min), the mean FR/CE and PA/CE ratios were higher in transgenic than in wild-type mice (1.06±0.04 vs 0.98±0.07, p=0.04; 1.06±0.09 vs 0.93±0.08 p=0.02) while ST/CE, TH/CE, and PO/CE ratios were not. Ex vivo staining revealed widespread Aβ plaques in cortex, but not in cerebellum of transgenic mice or in any brain regions of wild-type mice.

Conclusion

Marked reductions in brain uptake of this radioligand in transgenic mice may be due to reduced cerebral blood flow relative to that in wild-type mice. Specific [11C]6-OH-BTA-1 binding to Aβ plaques, if any, is probably very low, as reflected in the small FR/CE and PA/CE ratio differences. FR/CE and PA/CE ratios are considerably higher in AD patients while Aβ plaque densities in 22-month-old transgenic mice may be expected to show essentially the same density as is observed in the AD brain. This implies that the absence of tracer retention in 22-month-old transgenic mice may be due to the smaller number of Aβ plaque binding sites and/or to lower affinity of the binding sites for [11C]6-OH-BTA-1 as compared with AD patients. [11C]6-OH-BTA-1 shows excellent brain uptake in mice.

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References

  1. Kung HF, Kung MP, Zhuang ZP, Hou C, Lee CW, Plossl K, et al. Iodinated tracer for imaging amyloid plaques in the brain. Mol Imaging Biol 2003;5:418–26.

    Google Scholar 

  2. Scarpini E, Scheltens P, Feldman H. Treatment of Alzheimer’s disease: current status and new perspectives. Lancet Neurol 2003;2:539–47.

    Google Scholar 

  3. Minoshima S, Giordani B, Berent S, Frey KA, Foster NL, Kuhl DE. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease. Ann Neurol 1997;42:85–94.

    CAS  PubMed  Google Scholar 

  4. Kaneko K, Kuwabara Y, Sasaki M, Ogomori K, Ichimiya A, Koga H, et al. Posterior cingulate hypoperfusion in Alzheimer’s disease, senile dementia of Alzheimer type, and other dementias evaluated by three-dimensional stereotactic surface projections using Tc-99m HMPAO SPECT. Clin Nucl Med 2004;29:362–6.

    Google Scholar 

  5. Lee VMY. Tauists and Baptists united—well almost! Science 2001;293:1446–7.

    Google Scholar 

  6. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999;400:173–7.

    Article  CAS  PubMed  Google Scholar 

  7. Bacskai BJ, Klunk WE, Mathis CA, Hyman BT. Imaging amyloid-β deposits in vivo. J Cereb Blood Flow Metab 2002;22:1035–41.

    Google Scholar 

  8. Agdeppa ED, Kepe V, Liu J, Flores-Torres S, Satyamurthy N, Petric A, et al. Binding characteristics of radiofluorinated 6-dialkylamino-2-naphthylethylidene derivatives as positron emission tomography imaging probes for β-amyloid plaques in Alzheimer’s disease. J Neurosci 2001;21:RC189.

    Google Scholar 

  9. Kung M-P, Hou C, Zhuang Z-P, Zhang B, Skovronsky D, Trojanowski JQ, et al. IMPY: an improved thioflavin-T derivative for in vivo labeling of β-amyloid plaques. Brain Res 2002;956:202–10.

    Google Scholar 

  10. Mathis CA, Wang Y, Holt DP, Huang G-F, Debnath ML, Klunk WE. Synthesis and evaluation of 11C-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents. J Med Chem 2003;46:2740–54.

    Article  Google Scholar 

  11. Cai L, Chin FT, Pike VW, Toyama H, Liow JS, Zoghbi SS, et al. Synthesis and evaluation of two 18F-labeled 6-iodo-2-(4′-N,N-dimethylamino)phenylimidazo[1,2-a]pyridine derivatives as prospective radioligands for β-amyloid in Alzheimer’s disease. J Med Chem 2004;47:2208–18.

    Google Scholar 

  12. Verhoeff NPLG, Wilson AA, Takeshita S, Trop L, Hussey D, Singh K, et al. In-vivo imaging of Alzheimer disease β-amyloid with [11C]SB-13 PET. Am J Geriatr Psychiatry 2004;12:584–95.

    Google Scholar 

  13. Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compund-B. Ann Neurol 2004;55:306–19.

    Article  CAS  PubMed  Google Scholar 

  14. Chatziioannou AF. Molecular imaging of small animals with dedicated PET tomographs. Eur J Nucl Med Mol Imaging 2002;29 98–114.

    Article  PubMed  Google Scholar 

  15. Green MV, Seidel J, Vaquero JJ, Jagoda E, Lee I, Eckelman WC. High resolution PET, SPECT and projection imaging in small animals. Comput Med Imaging Graph 2001;25:79–86.

    Google Scholar 

  16. Toyama H, Ichise M, Liow JS, Vines DC, Seneca NM, Modell KJ, et al. Evaluation of anesthesia effects on [18F]FDG uptake in mouse brain and heart using small animal PET. Nucl Med Biol 2004;31:251–6.

    Google Scholar 

  17. Toyama H, Ichise M, Liow JS, et al. Absolute quantification of regional cerebral glucose utilization in mice by 18F-FDG small animal PET scanning and 2-14C-DG autoradiography. J Nucl Med 2004;45:1398–405.

    Google Scholar 

  18. Budinger TF, Benaron DA, Koretsky AP. Imaging transgenic animals. Annu Rev Biomed Eng 1999;1:611–48.

    Article  CAS  PubMed  Google Scholar 

  19. Cherry SR, Gambhir SS. Use of positron emission tomography in animal research. I LAR J 2001;42:219–32.

    Google Scholar 

  20. Wilson AA, Garcia A, Chestakova A, Kung H, Houle S. A rapid one-step radiosynthesis of the β-amyloid imaging radiotracer N-methyl-[11C]2-(4′-methylaminophenyl)-6- hydroxybenzothiazole ([11C]-6-OH-BTA-1). J Label Compd Radiopharm 2004;47:679–82.

    Google Scholar 

  21. Seidel J, Vaquero JJ, Green MV. Resolution uniformity and sensitivity of the NIH ATLAS small animal PET scanner: comparison to simulated LSO scanners without depth-of-interaction capability. IEEE Trans Nucl Sci 2003;50:1347–50.

    Google Scholar 

  22. Paxinos G, Franklin KBJ. The mouse brain in stereotaxic coordinates. 2nd ed. San Diego: Academic; 2001.

    Google Scholar 

  23. Kawarabayashi T, Younkin LH, Saido TC, Shoji M, Ashe KH, Younkin SG. Age-dependent changes in brain, CSF, and plasma amyloid β protein in the Tg2576 transgenic mouse model of Alzheimer’s disease. J Neurosci 2001;21:372–81.

    Google Scholar 

  24. Terai K, Iwai A, Kawabata S, Tasaki Y, Watanabe T, Miyata K, et al. β-amyloid deposits in transgenic mice expressing human β-amyloid precursor protein have the same characteristics as those in Alzheimer’s disease. Neuroscience 2001;104:299–310.

    Article  CAS  PubMed  Google Scholar 

  25. Kalback W, Watson MD, Kokjohn TA, Kuo YM, Weiss N, Luehrs DC, et al. APP transgenic mice Tg2576 accumulate Aβ peptides that are distinct from the chemically modified and insoluble peptides deposited in Alzheimer’s disease senile plaques. Biochemistry 2002;41:922–8.

    Google Scholar 

  26. Gravina SA, Ho L, Eckman CB, Long KE, Otvos L Jr, Younkin LH, et al. Amyloid β protein (Aβ) in Alzheimer’s disease brain: biochemical and immunocytochemical analysis with antibodies specific for forms ending at Aβ40 or Aβ42(43). J Biol Chem 1995;270:7013–6.

    Article  CAS  PubMed  Google Scholar 

  27. Klunk WE, Lopresti BJ, Debnath ML, Holt DP, Wang Y, Huang G, et al. Amyloid deposits in transgenic PS1/APP mice do not bind the amyloid PET tracer, PIB in the same manner as human brain amyloid. Neurobiology of Aging 2004;25(S2):232.

    Google Scholar 

  28. Hume SP, Myers R. Dedicated small animal scanners: a new tool for drug development? Curr Pharm Des 2002;8:1497–511.

    CAS  Google Scholar 

  29. Niwa K, Kazama K, Younkin SG, Carlson GA, Iadecola C. Alterations in cerebral blood flow and glucose utilization in mice overexpressing the amyloid precursor protein. Neurobiol Dis 2002;9:61–8.

    Google Scholar 

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Acknowledgements

We thank Dr. Chester A. Mathis, PhD, Department of Radiology, PET Facility, University of Pittsburgh for valuable suggestions.

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Correspondence to Hiroshi Toyama.

Additional information

This work was presented at the 51st Annual Meeting of the Society of Nuclear Medicine in Philadelphia, PA, June 19–23, 2004.

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Toyama, H., Ye, D., Ichise, M. et al. PET imaging of brain with the β-amyloid probe, [11C]6-OH-BTA-1, in a transgenic mouse model of Alzheimer’s disease. Eur J Nucl Med Mol Imaging 32, 593–600 (2005). https://doi.org/10.1007/s00259-005-1780-5

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  • DOI: https://doi.org/10.1007/s00259-005-1780-5

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