Amyloid Imaging Agents for Position Emission Tomography

Summary

Principal Investigator: Chester Mathis
Abstract: DESCRIPTION (provided by applicant): The proposed research involves the development of positron emission tomography (PET) radiopharmaceuticals that localize in the brain of human subjects based upon their selective binding to beta- sheet fibrils found in amyloid-beta (Ap) protein. The deposition of Ap in brain is believed to play a key role in the pathogenesis of Alzheimer's disease (AD). Our plan is to rationally design, synthesize, develop, and apply selective and potent A(3-binding fluorine-18-labeled PET radioligands capable of penetrating the blood- brain barrier and selectively binding to Ap deposits in the brains of living human subjects with high affinity. The structure of many of these radioligands is based upon lead compounds related chemically to the well known amyloid-selective dye Thioflavin T. It is anticipated that the application of the proposed 18F-labeled AP radioligands will make possible direct assessment of cerebral Ap burden and response to therapeutic strategies aimed at halting or reversing Ap deposition in the brains of human subjects. The 110 min half-life of the 18F-radionuclide label will make regional distribution of the Ap-specific PET radiopharmaceuticals practical in the same manner as has been realized for F-18-labeled FDG. Our specific aims include: 1) rationally design, synthesize, and evaluate the in vitro properties of a selected array of Ap-binding agents containing fluorine in a position that can be readily radiolabeled;2) radiolabel the most promising compounds with the high specific activity, positron-emitting radionuclide 18F;3) assess the in vivo properties of these radiotracers in normal control rodents;4) assess the in vivo properties of the 18F-labeled radiotracers in normal control baboons using PET imaging;5) take three 18F- labeled Ap agents into pilot human PET imaging studies in 5 AD and 5 age-matched control subjects to assess their in vivo imaging properties relative to the 11C-labeled AP radiotracer Pittsburgh Compound-B (PIB) in the same subjects;and 6) select one 18F-labeled amyloid agent to perform more extensive human PET imaging studies in 10 control subjects, 10 subjects with mild cognitive impairment (MCI), and 10 AD subjects, and compare its imaging properties to those of PIB.
Funding Period: ----------------2000 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Evaluation of voxel-based methods for the statistical analysis of PIB PET amyloid imaging studies in Alzheimer's disease
    Scott K Ziolko
    Department of Radiology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Rm B 938, PA 15213, USA
    Neuroimage 33:94-102. 2006
  2. pmc Development of positron emission tomography β-amyloid plaque imaging agents
    Chester A Mathis
    Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    Semin Nucl Med 42:423-32. 2012
  3. pmc Application of copulas to improve covariance estimation for partial least squares
    Gina M D'Angelo
    Division of Biostatistics, Washington University School of Medicine, St Louis, MO, U S A
    Stat Med 32:685-96. 2013
  4. pmc Using Pittsburgh Compound B for in vivo PET imaging of fibrillar amyloid-beta
    Ann D Cohen
    Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    Adv Pharmacol 64:27-81. 2012
  5. pmc In vivo assessment of amyloid-β deposition in nondemented very elderly subjects
    Chester A Mathis
    Department of Radiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
    Ann Neurol 73:751-61. 2013
  6. pmc Frequent amyloid deposition without significant cognitive impairment among the elderly
    Howard Jay Aizenstein
    Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    Arch Neurol 65:1509-17. 2008
  7. pmc The future of amyloid-beta imaging: a tale of radionuclides and tracer proliferation
    William E Klunk
    Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    Curr Opin Neurol 21:683-7. 2008
  8. pmc Imaging amyloid deposition in Lewy body diseases
    S N Gomperts
    Massachusetts General Hospital, Boston, MA 02114, USA
    Neurology 71:903-10. 2008
  9. pmc Characterizing regional correlation, laterality and symmetry of amyloid deposition in mild cognitive impairment and Alzheimer's disease with Pittsburgh Compound B
    Cyrus A Raji
    Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 2593, United States
    J Neurosci Methods 172:277-82. 2008
  10. pmc Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease
    Milos D Ikonomovic
    Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    Brain 131:1630-45. 2008

Scientific Experts

  • Timo Grimmer
  • W Jagust
  • Eric Reiman
  • Julie C Price
  • Andrew Saykin
  • Clayton A Wiley
  • David A Wolk
  • Kuo Shyan Lin
  • Bedda L Rosario
  • Chester A Mathis
  • William E Klunk
  • Brian J Lopresti
  • Steven T DeKosky
  • Ann D Cohen
  • Judith A Saxton
  • Scott K Ziolko
  • Lisa A Weissfeld
  • Beth E Snitz
  • Milos D Ikonomovic
  • Wenzhu Bi
  • Nicholas D Tsopelas
  • Jessica A Hoge
  • Gina M D'Angelo
  • Shanker Swaminathan
  • Howard J Aizenstein
  • REBECCA L MCNAMEE
  • Scott Ziolko
  • Robert D Nebes
  • Cyrus A Raji
  • S N Gomperts
  • Howard Jay Aizenstein
  • Eric M McDade
  • Oscar L Lopez
  • M Ilyas Kamboh
  • Lewis H Kuller
  • Steven G Potkin
  • Tatiana Foroud
  • Robert A Koeppe
  • Kwangsik Nho
  • David W Craig
  • Sungeun Kim
  • Clifford R Jack
  • Gil D Rabinovici
  • Li Shen
  • John D West
  • Karmen K Yoder
  • Mark Inlow
  • Michael W Weiner
  • Shannon L Risacher
  • Matthew J Huentelman
  • N Scott Mason
  • Seong Hwan Yee
  • Michael Berginc
  • Brian Lopresti
  • Jeffrey James
  • Howard A Aizenstein
  • Steven DeKosky
  • Lisa Weissfeld
  • Barbara A Isanski
  • W E Klunk
  • J J Locascio
  • Caroline E Hope
  • E Moran
  • K A Johnson
  • James T Becker
  • William R Paljug
  • J A Becker
  • A J Fischman
  • D M Rentz
  • Eric E Abrahamson
  • C A Mathis
  • Jeffrey A James
  • B T Hyman
  • Edythe M Halligan
  • Manik L Debnath
  • T Shoup
  • Patricia R Houck
  • Ronald L Hamilton
  • D R Elmaleh
  • J H Growdon
  • Dorene M Rentz
  • Joan M Swearer
  • Keith A Johnson
  • Daniel A Pollen
  • Carol F Lippa
  • Alan J Fischman
  • Majaz Moonis

Detail Information

Publications25

  1. ncbi Evaluation of voxel-based methods for the statistical analysis of PIB PET amyloid imaging studies in Alzheimer's disease
    Scott K Ziolko
    Department of Radiology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Rm B 938, PA 15213, USA
    Neuroimage 33:94-102. 2006
    ..These results indicate that voxel-based methods will be useful for future larger longitudinal studies of amyloid deposition that could improve AD diagnosis and anti-amyloid therapy assessment...
  2. pmc Development of positron emission tomography β-amyloid plaque imaging agents
    Chester A Mathis
    Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    Semin Nucl Med 42:423-32. 2012
    ..It is likely that the full clinical impact of these imaging agents will be realized by identifying presymptomatic subjects who would benefit from early drug treatments with future disease-modifying AD therapeutics...
  3. pmc Application of copulas to improve covariance estimation for partial least squares
    Gina M D'Angelo
    Division of Biostatistics, Washington University School of Medicine, St Louis, MO, U S A
    Stat Med 32:685-96. 2013
    ..Simulation studies show that the proposed estimator is an improvement over the standard estimators of covariance. We illustrate the methods from the motivating example from a study in the area of Alzheimer's disease...
  4. pmc Using Pittsburgh Compound B for in vivo PET imaging of fibrillar amyloid-beta
    Ann D Cohen
    Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    Adv Pharmacol 64:27-81. 2012
    ..Here, we will discuss the application of one of the most broadly studied and widely used Aβ imaging agents, Pittsburgh Compound-B (PiB)...
  5. pmc In vivo assessment of amyloid-β deposition in nondemented very elderly subjects
    Chester A Mathis
    Department of Radiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
    Ann Neurol 73:751-61. 2013
    ....
  6. pmc Frequent amyloid deposition without significant cognitive impairment among the elderly
    Howard Jay Aizenstein
    Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    Arch Neurol 65:1509-17. 2008
    ....
  7. pmc The future of amyloid-beta imaging: a tale of radionuclides and tracer proliferation
    William E Klunk
    Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    Curr Opin Neurol 21:683-7. 2008
    ....
  8. pmc Imaging amyloid deposition in Lewy body diseases
    S N Gomperts
    Massachusetts General Hospital, Boston, MA 02114, USA
    Neurology 71:903-10. 2008
    ..In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD)...
  9. pmc Characterizing regional correlation, laterality and symmetry of amyloid deposition in mild cognitive impairment and Alzheimer's disease with Pittsburgh Compound B
    Cyrus A Raji
    Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 2593, United States
    J Neurosci Methods 172:277-82. 2008
    ..02, p=0.01) and anterior ventral striatum [t(9)=2.37, p=0.04] in AD. No group differences (AD versus MCI) were detected in laterality [F (1, 15)=0.15, p=0.7] or asymmetry [F (1, 15)=0.7, p=0.42]...
  10. pmc Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease
    Milos D Ikonomovic
    Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    Brain 131:1630-45. 2008
    ..The strong direct correlation of in vivo PiB retention with region-matched quantitative analyses of Abeta plaques in the same subject supports the validity of PiB-PET imaging as a method for in vivo evaluation of Abeta plaque burden...
  11. pmc Impact of amyloid imaging on drug development in Alzheimer's disease
    Chester A Mathis
    Department of Radiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
    Nucl Med Biol 34:809-22. 2007
    ....
  12. pmc Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees
    William E Klunk
    Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
    J Neurosci 27:6174-84. 2007
    ..The early, focal striatal amyloid deposition observed in these PS1 mutation carriers is often is not associated with clinical symptoms...
  13. pmc Whatever happened to Pittsburgh Compound-A?
    William E Klunk
    Department of Psychiatry and Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    Alzheimer Dis Assoc Disord 22:198-203. 2008
  14. pmc Molecular brain imaging in the multimodality era
    Julie C Price
    Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    J Cereb Blood Flow Metab 32:1377-92. 2012
    ....
  15. pmc Amyloid pathway-based candidate gene analysis of [(11)C]PiB-PET in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort
    Shanker Swaminathan
    Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine, Indianapolis, IN, USA
    Brain Imaging Behav 6:1-15. 2012
    ..Pathway-based genetic analysis of targeted molecular imaging phenotypes appears promising to help elucidate disease pathophysiology and identify potential therapeutic targets...
  16. pmc Inter-rater reliability of manual and automated region-of-interest delineation for PiB PET
    Bedda L Rosario
    Department of Radiology, University of Pittsburgh School of Medicine, Presbyterian University Hospital, B 938, 200 Lothrop Street, Pittsburgh, PA 15213, USA
    Neuroimage 55:933-41. 2011
    ....
  17. pmc Progression of cerebral amyloid load is associated with the apolipoprotein E ε4 genotype in Alzheimer's disease
    Timo Grimmer
    Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar der Technischen Universitat Munchen, Munich, Federal Republic of Germany
    Biol Psychiatry 68:879-84. 2010
    ..Only few data have been published on in vivo longitudinal changes of amyloid load in Alzheimer's disease (AD) patients, with conflicting results. Therefore, little is known about the factors that influence these changes...
  18. pmc Basal cerebral metabolism may modulate the cognitive effects of Abeta in mild cognitive impairment: an example of brain reserve
    Ann D Cohen
    Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
    J Neurosci 29:14770-8. 2009
    ....
  19. pmc Relationships between biomarkers in aging and dementia
    W J Jagust
    Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94620, USA
    Neurology 73:1193-9. 2009
    ..Relationships between biomarkers and with disease severity are incompletely understood...
  20. pmc Amyloid imaging in mild cognitive impairment subtypes
    David A Wolk
    Alzheimer s Disease Research Center, University of Pittsburgh, Pittsburgh, PA 19104, USA
    Ann Neurol 65:557-68. 2009
    ....
  21. pmc Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease
    Eric M Reiman
    Banner Alzheimer s Institute and the Positron Emission Tomography Center, Good Samaritan Regional Medical Center, Phoenix, AZ 85006, USA
    Proc Natl Acad Sci U S A 106:6820-5. 2009
    ....
  22. pmc Beta amyloid in Alzheimer's disease: increased deposition in brain is reflected in reduced concentration in cerebrospinal fluid
    Timo Grimmer
    Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar der Technischen Universitat Munchen, Munich 81675, Germany
    Biol Psychiatry 65:927-34. 2009
    ..The aim of the study was to determine the association between cerebral amyloid plaque load, as measured by means of the positron emission tomography (PET) tracer carbon-11-labeled Pittsburgh Compound B ([11C]PiB) and CSF Abeta42 in AD...
  23. pmc Consideration of optimal time window for Pittsburgh compound B PET summed uptake measurements
    REBECCA L MCNAMEE
    Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    J Nucl Med 50:348-55. 2009
    ..In this work, regional PiB SUVRs were examined across 9 time windows to select the window that provided the best trade-offs between bias, correlation, and effective contrast...
  24. pmc Carbon 11-labeled Pittsburgh Compound B and carbon 11-labeled (R)-PK11195 positron emission tomographic imaging in Alzheimer disease
    Clayton A Wiley
    Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA
    Arch Neurol 66:60-7. 2009
    ..Because postmortem histopathological analyses are limited to single end-stage assessment, the time course and nature of this relationship are not well understood...
  25. pmc Synthesis and beta-amyloid binding properties of rhenium 2-phenylbenzothiazoles
    Kuo Shyan Lin
    Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15213, USA
    Bioorg Med Chem Lett 19:2258-62. 2009
    ....