Chet Mathis

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

Departments of Radiology, Pharmacology, and Pharmaceutical Sciences

University of Pittsburgh

Acknowledgments and Disclosures

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

The Definitive Biomarkers of AD:Amyloid- Plaques & Neurofibrillary TanglesImaged With the Highly Fluorescent Dye X-34

AD BrainFrontal Cortex

X-34

Elderly Control BrainFrontal Cortex

X-34 X-34

NFT

A PlaqueCerebral Amyloid Angiopathy

Neutral Thioflavin-T Analogues

Thioflavin-T [11C]PiB

A(1-40) Ki = 300 nM A(1-40) Ki = 2 nM

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

N

SN

CH3

CH3

H3C

CH3

+ N

SHON

11CH3

H

[11C]PiB in AD and Control

Very littleretention

Absence ofretention ingray matter

Appearance inexpected graymatter areas

Absence inareas wherethere isno amyloid

Dynamic Range of [11C]PiB

Lopresti et al., J Nucl Med 2005; 46:1959-72

120% difference in signal in PCG of ave. AD vs ave. Control

SUVR2.4

0

Future Clinical Imaging in DementiaC

og

nit

ive

Fu

nct

ion

Time

Normal Aging MCI AD

Current Imaging

Future Imaging

Adapted from Small et al., Lancet Neurol 2008

Amyloid Imaging in Mild Cognitive Impairment

Control MCI AD

Anticipated MCI Findings with PiB

Lopresti et al., J Nuclear Medicine 2005

MCI’s Cover the Range of Amyloid Load

Amyloid-Positivity Predicts Clinical Conversion in MCI

-Forsberg et al., Neurobiol Aging 2008-Wolk et al., Annals of Neurology 2009-Okello et al., Neurology 2009

1-2 years of follow-up in 115 MCI PiB+ AD Converters: 47/76 = 62% PiB- AD Converters: 2/39 = 5%

-Rowe et al., ICAD 2009

Amyloid Imaging in Normal Controls

FRC PRC LTC PAR MTC SWM

0

0.2

0.4

0.6

0.8

1

1.2

15

-20020

15

0.5

1.0

1.5

2.0

2.5

3.0

PIB

CE

R90

DV

R

0.5

1.0

1.5

2.0

2.5

3.0

PIB

CE

R90

DV

R

Fro

nta

l

Pre

cun

eus

Lat

. Tem

p

Par

ieta

l

Mes

ial T

emp

Su

bco

rt. W

M

AD range

Cntl range

Control AD

Some Elderly Controls are “PiB+”

HC

Neo

cort

ical

SU

VR

40-7

03.5

3.0

2.5

2.0

1.5

1.0

33%

Neo

cort

ical

SU

VR

40-7

03.5

3.0

2.5

2.0

1.5

1.0

n = 177Age = 73.6 ± 7.6MMSE = 28.8 ± 1.2

Frequency of PiB+ Among Elderly Healthy Controls:AIBL Study

ICAD 2009 V. Villamagne and C. Rowe

• Overall 20-40% prevalence >60 y/o normal controls

• 60-90 y/o increasing prevalence with age

• <55 y/o very low occurrence

Prevalence of PiB+ in Cognitively Normal Aging

Caveats

• PiB+ designation is somewhat artificial because amyloid exists in a continuum in the brain

• The detection threshold of PiB+ is not known

Longitudinal Follow-Up Studies

Logan DVR

1.0

2.0

Baseline 1 Yr 2 Yr

Longitudinal Studies of a Cognitively Normal Elderly Control

Longitudinal PiB PET Follow-up DataA Burden Change from Baseline: AIBL Study

1.0

1.2

1.4

1.6

1.8

2.0

2.2

2.4

2.6

2.8

3.0

3.2

3.4

AD(n=29)

MCI(n=35)

Ctrl(n=65)

Time (months)

0 20 37 0 20 37 0 20 371.0

1.2

1.4

1.6

1.8

2.0

2.2

2.4

2.6

2.8

3.0

3.2

3.4

1.0

1.2

1.4

1.6

1.8

2.0

2.2

2.4

2.6

2.8

3.0

3.2

3.4

Neo

cort

ical

SU

VR

40-7

0 1-4%per year

<1%per year

ICAD 2009 V. Villamagne and C. Rowe

Amyloid Imaging in Drug Development

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 A anti-body immunization

- - or -Secretase inhibitors

- Peripheral sink approaches

Anti-Amyloid Therapeutic Targets

Beta-AmyloidOLIGOMERS

PP

FIBRIL(-pleated sheet)

PLAQUE

BRAIN INFLAMMATION

NEUROTOXICITY33 Toxicity

Anti-oxidants, Vits E&C

Secretases11

Secretase Inhibitors

Clearance22A ImmunizationPeripheral Sinks

Baseline 20 45 78

Week

Cha

nge

in [

11C

]PiB

0

0.3

0.1

0.2

-0.1

-0.2

p = 0.003

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

Post-Mortem Correlations

Correlating PiB Retention In Vivo with A Levels Determined Post-Mortem

Ikonomovic et al., Brain 2008

• 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

CASE #1

Correlation of PiB Retention In Vivo with A Levels Determined Post-Mortem

Ikonomovic et al., Brain 2008

11

22

33

44

55

66

77

88

99

1010

1111

1212

1313

14141515

16161717

1818

19192020

21212222

2323

2424

2525

11

22

33

44

55

66

77

88

99

1010

1111

1212

1313

14141515

16161717

1818

19192020

21212222

2323

2424

2525

PiB Retention In Vivo Corelates Well with A Levels Determined Post-Mortem

Ikonomovic et al., Brain 2008

Frozen Tissue (right hemisphere)

Chart Title

0.8

1.1

1.4

1.7

2.0

2.3

2.6

0 0.5 1 1.5 2

A 1-42 (pmol/mg tissue)

In V

ivo

PiB

Ret

enti

on

(D

VR

)

0 0.5 1.0 1.5 2.0

Total Insoluble A (pmol/mg tissue)

Frozen Tissue (right hemisphere)

0.8

1.4

2.0

2.6

In V

ivo

PiB

Ret

enti

on

(D

VR

)

r = 0.73, p<0.0028

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-A drug trials

Improved Amyloid-beta Radiotracers

PiB for Amyloid Imaging

Two areas for improvement:

• 20 min half-life of 11C radiolabel

• non-specific retention in white matter

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

HN

O

CH3

O

O 18F

[18F]AV-1 / BAY94-9172

florbetaben

KD = 6.7 nMAD brain

2007

2008

[18F]AV-45

florbetapir

HN

O

CH3

O

O 18FN

KD = 3.1 nMAD brain

New 18F-Labeled Amyloid Radiotracers

[18F]3’F-PIB / GE-067

flutemetamol

2007KD = 2.2 nM

AD brainN

S HO

NH

CH3

18F

[18F]florbetaben

Rowe et al., Lancet Neurol 2008;7:129–35

Elderly Control AD

[18F]florbetapir

Images courtesy of Dan Skovronsky, Avid Radiopharmaceuticals

Control

AD

Comparison of [18F]flutemetamol and [11C]PiB in the same control and AD subject

CONTROL AD

[18F]flutemetamol

[11C]PiB

90-120 min

40-90 min

0.5

2.5

0.5

2.5

SUVR

SUVR

1.0

1.5

2.0

2.5

3.0

[11C]PiB [18F]florbetaben(BAY94-9172)

(AV-1)

[18F]flutemetamol(GE-067)

(3’-F-PiB)

[18F]florbetapir (AV-45)

120%

69%

70%

66%

Lopresti et al., 2005

Rowe et al., 2008

Mathis et al., 2007

Wong et al., 2008

AD

AD

AD

AD

NCNC

NC

NC

SU

VR

Signal : AD vs. Normal Control in PCG

Sub-Cortical White Matter Retention

36%75%

75%

75%

Ichise et al., 2008

Lin et al., 2010

Future Clinical Imaging in DementiaC

og

nit

ive

Fu

nct

ion

Time

Normal Aging MCI AD

Current Imaging

Future Imaging

Adapted from Small et al., Lancet Neurol 2008

Future Challenges

• Develop selective and potent NFT radioligands to complement A radioligands

• Conduct definitive longitudinal studies to fully elucidate the time course and linkage of A deposition to cognitive decline

• Define the detection sensitivity of A imaging agents in terms of regional concentrations of insoluble and total A

• Use A imaging to identify subjects who would most benefit from anti-A therapies and document the efficacy of anti-A therapies and subsequent patient improvement or stabilization

Amyloid Imaging Project Collaborators

• PET Facility

- Julie Price

- Scott Mason

- Daniel Holt

- Brian Lopresti

- Guo-feng Huang

• Molecular Neuropharm Lab

- Bill Klunk- Manik Debnath

- Li Shao

• ADRC

- Steve DeKosky, prev. Director

- Oscar Lopez, current Director

- Milos Ikonomovic

- Ron Hamilton, Bill Paljug

• GEHC

- Gill Farrar

- Kim Gallagher

[18F]FDDNP: 10% Increase in Signalin MTC of AD vs Control

(binds to both A plaques and NFT)

Shoghi-Jadid et al., AJGP 2002;10:24-35 Small et al., NEJM 2006;355:2652-63

Con

trol

Con

trol

MC

I

MC

I

AD

AD

Con

trol

Con

trol

MC

I

MC

I

AD

AD

Lopresti et al.JNM 2005[11C]PiB

Small et al.NEJM 2006[18F]FDDNP

1.0

1.5

2.0

2.5

3.0

DV

R

Comparison of the Dynamic Range of PiB and FDDNP

PCG MTC