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Human Amyloid-beta Imaging in Alzheimer’s Disease: Future Tracer Development

Human Amyloid-beta Imaging in Alzheimer’s Disease: Future Tracer Development. Chet Mathis. Departments of Radiology, Pharmacology, and Pharmaceutical Sciences University of Pittsburgh. Funding and Conflicts • NIH: NIA & NIMH • Alzheimer’s Association • US Department of Energy

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Human Amyloid-beta Imaging in Alzheimer’s Disease: Future Tracer Development

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  1. Human Amyloid-beta Imaging in Alzheimer’s Disease:Future Tracer Development Chet Mathis Departments of Radiology, Pharmacology, and Pharmaceutical Sciences University of Pittsburgh

  2. Funding and Conflicts • • NIH: NIA & NIMH • • Alzheimer’s Association • • US Department of Energy • Dana Foundation • • GE Healthcare • - licensed technology from University of Pittsburgh • - conflict of interest as a co-inventor of technology • - PiB is freely available to academic investigators, but its • commercial use is subject to GE Healthcare approval Acknowledgments and Disclosures

  3. AD Brain Frontal Cortex Elderly Control Brain Frontal Cortex X-34 The Definitive Biomarkers of AD: Amyloid-b Plaques & Neurofibrillary Tangles Imaged With the Highly Fluorescent Dye X-34 X-34 X-34 NFT Cerebral Amyloid Angiopathy Ab Plaque

  4. Ab(1-40) Ki = 2 nM Ab(1-40) Ki = 300 nM Neutral Thioflavin-T Analogues HO H C S S C H 11CH3 3 3 N N + C H N H N 3 C H 3 Thioflavin-T [11C]PiB Klunk et al., Life Sci 2001; Mathis et al., Bioorg Med Chem Lett 2002; Klunk et al., J Neurosci 2003; Mathis et al., J Med Chem 2003; Klunk et al., Ann Neurology 2004; Mathis et al., Curr Pharm Design 2004

  5. [11C]PiB in AD and Control Appearance inexpected graymatter areas Very littleretention Absence inareas wherethere isno amyloid Absence ofretention ingray matter

  6. Dynamic Range of [11C]PiB 120% difference in signal in PCG of ave. AD vs ave. Control SUVR 2.4 0 Lopresti et al., J Nucl Med 2005; 46:1959-72

  7. Time Future Clinical Imaging in Dementia MCI Normal Aging AD Cognitive Function Future Imaging Current Imaging Adapted from Small et al., Lancet Neurol 2008

  8. Amyloid Imaging in Mild Cognitive Impairment

  9. Anticipated MCI Findings with PiB Control MCI AD

  10. MCI’s Cover the Range of Amyloid Load Lopresti et al., J Nuclear Medicine 2005

  11. Amyloid-Positivity Predicts Clinical Conversion in MCI -Forsberg et al., Neurobiol Aging 2008 -Wolk et al., Annals of Neurology2009 -Okello et al., Neurology 2009 -Rowe et al., ICAD 2009 1-2 years of follow-up in 115 MCI PiB+ AD Converters: 47/76 = 62% PiB- AD Converters: 2/39 = 5%

  12. Amyloid Imaging in Normal Controls

  13. AD range Control AD Cntl range Frontal Parietal Lat. Temp Precuneus Mesial Temp Subcort. WM Some Elderly Controls are “PiB+”

  14. Frequency of PiB+ Among Elderly Healthy Controls: AIBL Study n = 177 Age = 73.6 ± 7.6 MMSE = 28.8 ± 1.2 3.5 3.5 3.0 3.0 2.5 2.5 Neocortical SUVR40-70 Neocortical SUVR40-70 33% 2.0 2.0 1.5 1.5 1.0 1.0 HC ICAD 2009 V. Villamagne and C. Rowe

  15. Prevalence of PiB+ in Cognitively Normal Aging • Overall 20-40% prevalence >60 y/o normal controls • 60-90 y/o increasing prevalence with age • <55 y/o very low occurrence • Caveats • PiB+ designation is somewhat artificial because amyloid exists • in a continuum in the brain • The detection threshold of PiB+ is not known

  16. Longitudinal Follow-Up Studies

  17. Logan DVR 2.0 1.0 Longitudinal Studies of a Cognitively Normal Elderly Control Baseline 1 Yr 2 Yr

  18. 3.4 3.4 3.4 3.2 3.2 3.2 3.0 3.0 3.0 2.8 2.8 2.8 2.6 2.6 2.6 2.4 2.4 2.4 2.2 2.2 2.2 2.0 2.0 2.0 1.8 1.8 1.8 1.6 1.6 1.6 1.4 1.4 1.4 1.2 1.2 1.2 1.0 1.0 1.0 0 0 0 20 20 20 37 37 37 Longitudinal PiB PET Follow-up Data Ab Burden Change from Baseline: AIBL Study Ctrl (n=65) MCI (n=35) AD (n=29) 1-4% per year Neocortical SUVR40-70 <1% per year Time (months) ICAD 2009 V. Villamagne and C. Rowe

  19. Amyloid Imaging in Drug Development

  20. Early Detection of Amyloid Deposits • Will become very important if effective therapies are available to prevent or slow AD progression • Current therapies showing the most promise • Active or passive Ab anti-body immunization • b- or g-Secretase inhibitors • Peripheral sink approaches

  21. Clearance APP g Ab Immunization Peripheral Sinks b # # Secretases Beta-Amyloid OLIGOMERS 1 2 Secretase Inhibitors PLAQUE NEUROTOXICITY Toxicity FIBRIL (b-pleated sheet) 3 Anti-oxidants, Vits E&C BRAIN INFLAMMATION Anti-Amyloid Therapeutic Targets

  22. 0.3 0.2 0.1 Change in [11C]PiB p = 0.003 0 -0.1 -0.2 Baseline 20 45 78 Week Change in Fibrillar Amyloid-β Load in Alzheimer’s Disease Subjects Treated with the Anti-body Bapineuzumab Phase II Results Rinne et al., Lancet Neurology 2010

  23. Post-Mortem Correlations

  24. Correlating PiB Retention In Vivo with A Levels Determined Post-Mortem CASE #1 • 61 year old female with severe AD • Followed for 1 year at Univ. of Pittsburgh ADRC • MMSE = 1 at last visit • Died 10 months after PiB scan Ikonomovic et al., Brain 2008

  25. Correlation of PiB Retention In Vivo with A Levels Determined Post-Mortem Ikonomovic et al., Brain 2008

  26. PiB Retention In Vivo Corelates Well with A Levels Determined Post-Mortem Frozen Tissue (right hemisphere) Frozen Tissue (right hemisphere) 2.6 2.0 In Vivo PiB Retention (DVR) 1.4 r = 0.73, p<0.0028 0.8 0 2.0 1.0 1.5 0.5 Total Insoluble Ab (pmol/mg tissue) Ikonomovic et al., Brain 2008

  27. Ongoing Studies with PiB • World-wide • •>60 PET sites presently conducting PiB studies • •>8,000 PiB scans performed • Univ Pittsburgh • •>600 PiB scans performed • •Conducting longitudinal studies in normal aging, MCI & AD • •Correlating with FDG scans and cognitive scores • • Correlating PiB scans with post-mortem analyses • Selected World Sites • •Utilizing as a biomarker in anti-Ab drug trials

  28. Improved Amyloid-beta Radiotracers

  29. PiB for Amyloid Imaging • Two areas for improvement: • 20 min half-life of 11C radiolabel • non-specific retention in white matter

  30. Studies with 18F-Labeled Amyloid Tracers • • Greater distribution potential than 11C-radiolabel • 110 min vs 20 min half-life • • Phase III human studies in progress at Avid, GEHC • & Bayer-Schering

  31. 1 8 F O H H C S 3 H N N C H 3 1 8 H N O F C H 3 N 1 8 O O H N O F O O New 18F-Labeled Amyloid Radiotracers KD = 2.2 nM AD brain 2007 [18F]3’F-PIB / GE-067 flutemetamol 2007 KD = 6.7 nM AD brain [18F]AV-1 / BAY94-9172 florbetaben 2008 KD = 3.1 nM AD brain [18F]AV-45 florbetapir

  32. [18F]florbetaben AD Elderly Control Rowe et al., Lancet Neurol 2008;7:129–35

  33. [18F]florbetapir Control AD Images courtesy of Dan Skovronsky, Avid Radiopharmaceuticals

  34. 2.5 2.5 0.5 0.5 Comparison of [18F]flutemetamol and [11C]PiB in the same control and AD subject CONTROL AD SUVR [18F]flutemetamol 90-120 min SUVR [11C]PiB 40-90 min

  35. 70% 120% AD AD 75% 69% 66% AD AD 75% 75% 36% NC NC NC NC Signal : AD vs. Normal Control in PCG Sub-CorticalWhite Matter Retention 3.0 2.5 SUVR 2.0 1.5 1.0 [11C]PiB [18F]florbetaben(BAY94-9172) (AV-1) [18F]flutemetamol(GE-067) (3’-F-PiB) [18F]florbetapir (AV-45) Wong et al., 2008 Lopresti et al., 2005 Mathis et al., 2007 Rowe et al., 2008 Ichise et al., 2008 Lin et al., 2010

  36. Time Future Clinical Imaging in Dementia MCI Normal Aging AD Cognitive Function Future Imaging Current Imaging Adapted from Small et al., Lancet Neurol 2008

  37. Future Challenges • Develop selective and potent NFT radioligands to complement Ab radioligands • Conduct definitive longitudinal studies to fully elucidate the time course and linkage of Ab deposition to cognitive decline • Define the detection sensitivity of Ab imaging agents in terms of regional concentrations of insoluble and total Ab • Use Ab imaging to identify subjects who would most benefit from anti-Ab therapies and document the efficacy of anti-Ab therapies and subsequent patient improvement or stabilization

  38. Amyloid Imaging Project Collaborators • ADRC • Steve DeKosky, prev. Director • Oscar Lopez, current Director • Milos Ikonomovic • Ron Hamilton, Bill Paljug • GEHC • Gill Farrar • Kim Gallagher • PET Facility • Julie Price • Scott Mason • Daniel Holt • Brian Lopresti • Guo-feng Huang • Molecular Neuropharm Lab • Bill Klunk • Manik Debnath • Li Shao

  39. [18F]FDDNP: 10% Increase in Signalin MTC of AD vs Control(binds to both Ab plaques and NFT) Shoghi-Jadid et al., AJGP 2002;10:24-35 Small et al., NEJM 2006;355:2652-63

  40. Comparison of the Dynamic Range of PiB and FDDNP MTC PCG

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