Smart optical probes for near-infrared fluorescence imaging of Alzheimer’s disease pathology

  • Scott B. Raymond
  • Jesse Skoch
  • Ivory D. Hills
  • Evgueni E. Nesterov
  • Timothy M. Swager
  • Brian J. Bacskai
Article

Abstract

Purpose

Near-infrared fluorescent probes for amyloid-beta (Aβ) are an exciting option for molecular imaging in Alzheimer’s disease research and may translate to clinical diagnostics. However, Aβ-targeted optical probes often suffer from poor specificity and slow clearance from the brain. We are designing smart optical probes that emit characteristic fluorescence signal only when bound to Aβ.

Methods

We synthesized a family of dyes and tested Aβ-binding sensitivity with fluorescence spectroscopy and tissue-staining.

Results

Select compounds exhibited Aβ-dependent changes in fluorescence quantum yield, lifetime, and emission spectra that may be imaged microscopically or in vivo using new lifetime and spectral fluorescence imaging techniques.

Conclusion

Smart optical probes that turn on when bound to Aβ will improve amyloid detection and may enable quantitative molecular imaging in vivo.

Keywords

Optical probes Fluorescence imaging Alzheimer’s disease Near-infrared 

References

  1. 1.
    Hyman BT, Trojanowski JQ. Consensus recommendations for the postmortem diagnosis of Alzheimer disease from the National Institute on Aging and the Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer disease. J Neuropathol Exp Neurol. 1997;56(10):1095–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature. 1995;373(6514):523–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Hsiao KK, Borchelt DR, Olson K, Johannsdottir R, Kitt C, Yunis W, et al. Age-related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins. Neuron. 1995;15(5):1203–18.PubMedCrossRefGoogle Scholar
  4. 4.
    Spires TL, Hyman BT. Neuronal structure is altered by amyloid plaques. Rev Neurosci. 2004;15(4):267–78.PubMedGoogle Scholar
  5. 5.
    Poduslo JF, Wengenack TM, Curran GL, Wisniewski T, Sigurdsson EM, Macura SI, et al. Molecular targeting of Alzheimer’s amyloid plaques for contrast-enhanced magnetic resonance imaging. Neurobiol Dis. 2002;11(2):315–29.PubMedCrossRefGoogle Scholar
  6. 6.
    Higuchi M, Iwata N, Matsuba Y, Sato K, Sasamoto K, Saido TC. 19F and 1H MRI detection of amyloid beta plaques in vivo. Nat Neurosci. 2005;8(4):527–33.PubMedCrossRefGoogle Scholar
  7. 7.
    Shoghi-Jadid K, Small GW, Agdeppa ED, Kepe V, Ercoli LM, Siddarth P, et al. Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. Am J Geriatr Psychiatry. 2002;10(1):24–35.PubMedGoogle Scholar
  8. 8.
    Ono M, Wilson A, Nobrega J, Westaway D, Verhoeff P, Zhuang ZP, et al. 11C-labeled stilbene derivatives as Abeta-aggregate-specific PET imaging agents for Alzheimer's disease. Nucl Med Biol. 2003;30(6):565–71.PubMedCrossRefGoogle Scholar
  9. 9.
    Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol. 2004;55(3):306–19.PubMedCrossRefGoogle Scholar
  10. 10.
    Engler H, Forsberg A, Almkvist O, Blomquist G, Larsson E, Savitcheva I, et al. Two-year follow-up of amyloid deposition in patients with Alzheimer’s disease. Brain. 2006;129(11):2856–66.PubMedCrossRefGoogle Scholar
  11. 11.
    Rowe CC, Ng S, Ackermann U, Gong SJ, Pike K, Savage G, et al. Imaging beta-amyloid burden in aging and dementia. Neurology. 2007;68(20):1718–25.PubMedCrossRefGoogle Scholar
  12. 12.
    Hintersteiner M, Enz A, Frey P, Jaton AL, Kinzy W, Kneuer R, et al. In vivo detection of amyloid-beta deposits by near-infrared imaging using an oxazine-derivative probe. Nat Biotechnol. 2005;23(5):577–83.PubMedCrossRefGoogle Scholar
  13. 13.
    Nesterov EE, Skoch J, Hyman BT, Klunk WE, Bacskai BJ, Swager TM. In vivo optical imaging of amyloid aggregates in brain: design of fluorescent markers. Angew Chem Int Ed Engl. 2005;44(34):5452–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Godavarty A, Sevick-Muraca EM, Eppstein MJ. Three-dimensional fluorescence lifetime tomography. Med Phys. 2005;32(4):992–1000.PubMedCrossRefGoogle Scholar
  15. 15.
    Kumar AT, Skoch J, Bacskai BJ, Boas DA, Dunn AK. Fluorescence-lifetime-based tomography for turbid media. Opt Lett. 2005;30(24):3347–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Zavattini G, Vecchi S, Mitchell G, Weisser U, Leahy RM, Pichler BJ, et al. A hyperspectral fluorescence system for 3D in vivo optical imaging. Phys Med Biol. 2006;51(8):2029–43.PubMedCrossRefGoogle Scholar
  17. 17.
    Dunphy I, Vinogradov SA, Wilson DF. Oxyphor R2 and G2: phosphors for measuring oxygen by oxygen-dependent quenching of phosphorescence. Anal Biochem. 2002;310(2):191–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Wilms CD, Eilers J. Photo-physical properties of Ca2+indicator dyes suitable for two-photon fluorescence-lifetime recordings. J Microsc. 2007;225(Pt 3):209–13.PubMedCrossRefGoogle Scholar
  19. 19.
    Berezin MY, Lee H, Akers W, Achilefu S. Near infrared dyes as lifetime solvatochromic probes for micropolarity measurements of biological systems. Biophys J. 2007;93(8):2892–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Venkatraman P, Nguyen TT, Sainlos M, Bilsel O, Chitta S, Imperiali B, et al. Fluorogenic probes for monitoring peptide binding to class II MHC proteins in living cells. Nat Chem Biol. 2007;3(4):222–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Olmsted J III. Calorimetric determination of absolute fluorescence quantum yields. J Phys Chem. 1979;83(20):2581–4.CrossRefGoogle Scholar
  22. 22.
    LeVine H 3rd. Thioflavine T interaction with synthetic Alzheimer’s disease beta-amyloid peptides: detection of amyloid aggregation in solution. Protein Sci. 1993;2(3):404–10.PubMedCrossRefGoogle Scholar
  23. 23.
    Voropai ES, Samtsov MP, Kaplevskii KN, Maskevich AA, Stepuro VI, Povarova OI, et al. Spectral properties of Thioflavin T and its complexes with amyloid fibrils. J Appl Spectrosc. 2003;70(6):868–74.CrossRefGoogle Scholar
  24. 24.
    Kumar ATN, Raymond SB, Boverman G, Boas DA, Bacskai BJ. Time resolved fluorescence tomography based on lifetime contrast. Opt Express. 2006;14:12255.CrossRefPubMedGoogle Scholar
  25. 25.
    Levenson RM, Mansfield JR. Multispectral imaging in biology and medicine: slices of life. Cytometry A. 2006;69(8):748–58.PubMedGoogle Scholar
  26. 26.
    Tam JM, Upadhyay R, Pittet MJ, Weissleder R, Mahmood U. Improved in vivo whole-animal detection limits of green fluorescent protein-expressing tumor lines by spectral fluorescence imaging. Mol Imaging. 2007;6(4):269–76.PubMedGoogle Scholar
  27. 27.
    Mathis CA, Wang Y, Klunk WE. Imaging beta-amyloid plaques and neurofibrillary tangles in the aging human brain. Curr Pharm Des. 2004;10(13):1469–92.PubMedCrossRefGoogle Scholar
  28. 28.
    Wang Y, Mathis CA, Huang GF, Debnath ML, Holt DP, Shao L, Klunk WE. Effects of lipophilicity on the affinity and nonspecific binding of iodinated benzothiazole derivatives. J Mol Neurosci. 2003;20(3):255–60.PubMedCrossRefGoogle Scholar
  29. 29.
    Groenning M, Norrman M, Flink JM, van de Weert M, Bukrinsky JT, Schluckebier G, et al. Binding mode of Thioflavin T in insulin amyloid fibrils. J Struct Biol. 2007;159(3):483–97.PubMedCrossRefGoogle Scholar
  30. 30.
    Groenning M, Olsen L, van de Weert M, Flink JM, Frokjaer S, Jargensen FS. Study on the binding of Thioflavin T to beta-sheet-rich and non-beta-sheet cavities. J Struct Biol. 2007;158(3):358–69.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Scott B. Raymond
    • 1
  • Jesse Skoch
    • 2
  • Ivory D. Hills
    • 4
  • Evgueni E. Nesterov
    • 3
  • Timothy M. Swager
    • 4
  • Brian J. Bacskai
    • 1
  1. 1.Alzheimer’s Disease Research UnitDepartment of Neurology, Massachusetts General HospitalCharlestownUSA
  2. 2.Department of PharmacologyUniversity of Colorado at Denver and Health Sciences CenterDenverUSA
  3. 3.Department of ChemistryLouisiana State UniversityBaton RougeUSA
  4. 4.Department of Chemistry and Institute for Soldier NanotechnologiesMassachusetts Institute of TechnologyCambridgeUSA

Personalised recommendations