PET/SPECT Imaging of Multidrug Resistance
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PET/SPECT Imaging of Multidrug Resistance P-glycoprotein: Transport Activity Monitoring Associated with Blood-Brain Barrier Function David Piwnica -Worms, M.D., Ph.D. Director, Molecular Imaging Center Mallinckrodt Institute of Radiology and Department of Developmental Biology

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PET/SPECT Imaging of Multidrug Resistance P-glycoprotein:

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Pet spect imaging of multidrug resistance p glycoprotein

PET/SPECT Imaging of Multidrug Resistance

P-glycoprotein:

Transport Activity Monitoring Associated with Blood-Brain Barrier Function

David Piwnica-Worms, M.D., Ph.D.

Director, Molecular Imaging Center

Mallinckrodt Institute of Radiology

and

Department of Developmental Biology

Washington University Medical School

St. Louis, MO


Pet spect imaging of multidrug resistance p glycoprotein

Molecular Imaging of Drug Transport In Vivo:

Multidrug Resistance (MDR1) P-glycoprotein

-Efflux transporter

-Normally expressed in liver, kidney, bowels,

choroid plexus, capillaries of BBB

-Pumps xenobiotics and cancer chemotherapeutic

drugs out of MDR cancer cells and

prevents drugs from entering brain via BBB

-MDR drugs include: taxol, doxorubicin,

vinblastine, vincristine, VP16, TKI’s

(e.g., Gleevec), HIV protease inhibitors,

antibiotics, antidepressants, peptides,

lipophiliccations

-Pumps b-amyloid out of the brain across BBB

-MDR modulators (inhibitors) in clinical trials

-MDR1 polymorphisms impact drug PK/PD

Immunotech


Pet spect imaging of multidrug resistance p glycoprotein

Crystal Structure: Mouse P-Glycoprotein

Front View

Back View

Probable Model for Transport

of Recognized Substrates

Science 2009, 323, 1718-1723


Pet spect imaging of multidrug resistance p glycoprotein

Radiopharmaceuticals Targeting MDR1 P-glycoprotein

SPECT AgentsPET Agents

99mTc-Sestamibi

99mTc -Tetrofosmin

99mTc-Q58, 99mTc-Q63

99mTc-CO-mibi

67Ga-ENBPI

68Ga-ENBPI

64Cu-dioxime

11C-verapamil

11C-daunorubicin

11C-colchicine

94mTc-Sestamibi

18F-paclitaxol

11C-loperamide


Pet spect imaging of multidrug resistance p glycoprotein

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Conventional Radiopharmaceuticals Targeting MDR1 P-glycoprotein


Conventional spect agents recognized by mdr1 pgp as transport substrates

Conventional SPECT Agents Recognized by MDR1Pgpas Transport Substrates


Pet spect imaging of multidrug resistance p glycoprotein

New SPECT Agent Recognized by MDR1Pgpas a Transport Substrate

67Ga-ENBPI


Pet spect imaging of multidrug resistance p glycoprotein

New PET Agent Recognized by MDR1Pgpas a Transport Substrate

11C-Loperamide

Robert Innis, et al.


Pet spect imaging of multidrug resistance p glycoprotein

MDR

+ Inh

wt

max

ADP

MDR1 P-glycoprotein

Tc-Complex

MDR

ATP

(-)

min

High Potency MDR

Inhibitors:

Cell Uptake

Glaxo GG918

Novartis PSC 833

Vertex 710

Eli Lilly 335979

XR9576

  • MODEL OF [99mTc]-SESTAMIBI ACCUMULATION

  • IN TUMOR CELLS:

  • MEMBRANE POTENTIAL-DRIVEN PASSIVE INFLUX

  • MDR1 P-GLYCOPROTEIN-MEDIATED EFFLUX TRANSPORT

cell membrane

Tc-Complex

Tc-Complex

mito


Pet spect imaging of multidrug resistance p glycoprotein

Electron Probe X-ray Microanalysis (EPXMA)

of a Cultured Heart Cell Incubated in Technetium-99-Sestamibi

Electron Density Map Technetium Map

Mitochondrial rich tissue; No P-glycoprotein expression


Pet spect imaging of multidrug resistance p glycoprotein

Pgp

o

WILD TYPE VIRUS

300

Sf9 MDR1 WT

Tc-SESTAMIBI CONTENT ( fmol / mg protein nM )

200

Pgp-

100

RECOMBINANT MDR1

TIME (min)

0

[99mTc]-Sestamibi

0

10

20

30

40

50

60

Baculoviral Expression of Recombinant Human MDR1 in Host Sf9 Cells:

Effect on [99mTc]-Sestamibi Accumulation


Pet spect imaging of multidrug resistance p glycoprotein

ABC Transporter-Mediated Efflux of [99mTc]-Sestamibi

In Cultured Cell Monolayer Assays

High Avidity Transport

MDR1 Pgp

Modest Avidity Transport

MRP1

Minimal or Non-detectable Transport

MDR3 Pgp

MRP2, MRP3, MRP4, MRP5, MRP6

BCRP1/MXR


Pet spect imaging of multidrug resistance p glycoprotein

[99mTc]-Sestamibi

Imaging MDR1 P-glycoprotein Transport Activity in

Breast Cancer: Dynamic [99mTc]-Sestamibi Mammoscintigraphy

1 hr post-injection

1° Tumor

4 hr post-injection


Pet spect imaging of multidrug resistance p glycoprotein

[99mTc]-Sestamibi Clearance From Breast Cancers In Vivo

Low Pgp

High Pgp

Del Vecchio, et al, Eur J Nucl Med 24:150, 1997


Pet spect imaging of multidrug resistance p glycoprotein

Pgp Expressed Only on the Luminal Surface of Brain Capillaries:

Provides Unidirectional Drug Transport Function at the BBB

BBB

Blood

CSF

Pgp

Drug Barrier

Compound Efflux

Capillary Endothelial Cells


Pet spect imaging of multidrug resistance p glycoprotein

Functional Demonstration of the Drug-Permeability Barrier

at the BBB in Humans with 99mTc-Sestamibi

T1 MRI

Co-Registration

Tc-MIBI SPECT

PNAS, 1999


Pet spect imaging of multidrug resistance p glycoprotein

Functional Demonstration of the Drug-Permeability Barrier

at the BBB in Humans with 11C-Verapamil

Sasongko, et al, 2005


Pet spect imaging of multidrug resistance p glycoprotein

Functional Demonstration of the Drug-Permeability Barrier

at the BBB in Humans with 11C-Loperamide

Lop

11C-N-Desmethyl-Loperamide

Robert Innis, et al., 2009


Pet spect imaging of multidrug resistance p glycoprotein

WT mdr1a/1b-/-

brain

mdr1a/1b-/-

WT

MicroPET: 10 min p.i.

Biodistribution Analysis

Molecular Imaging of mdr1 P-glycoprotein Transport Activity

at the Capillary Blood-Brain Barrier in vivo with ENBPI Ga-Complexes:

Correlation between Biodistribution and MicroPET Analysis

68Ga-3EtO-ENBPI


Pet spect imaging of multidrug resistance p glycoprotein

Bidirectional Dynamic Model for Influx and Efflux

of b-Amyloid (Aβ) Across the BBB:

Pgp Transports b-Amyloid out of the CNS


Pet spect imaging of multidrug resistance p glycoprotein

Pgp-null mice microinjected into CNS with b-Amyloid:

Enhanced retention and reduced clearance from the brain

Acute inhibition of Pgp with XR9576:

Enhancement of CNS b-Amyloid content

Enhanced amyloid plaque content in aged APPsw, Pgp-null mice

mdr1 P-glycoprotein Deficiency at the Blood Brain Barrier Increases b-Amyloid Deposition in an Alzheimer Disease Mouse Model:P-glycoprotein Pumps b-Amyloid out of the Brain

J Clin Invest 115: 3285, 2005


Pet spect imaging of multidrug resistance p glycoprotein

APPsw/PS1-PgpWT

APPsw/PS1-Pgp Null

NanoSPECT Imaging: Comparative Uptake of 99mTc-Sestamibi inAPPsw/PS1-PgpWT and APPsw/PS1-Pgp-Null Mice

Brain

2h Post Injection; 3-months old mice


Pet spect imaging of multidrug resistance p glycoprotein

[99mTc]-Sestamibi

Molecular Imaging of Multidrug Resistance (MDR1) P-glycoprotein (Pgp)

Transport Activity at the BBB

Pgp

  • Pgp pumps drugs and substrates

  • off the plasma membrane

  • Several PET and SPECT tracers show promise

    • as transport substrates for monitoring Pgp

  • Pgp is an important component of the BBB

  • and can be functionally imaged by

  • PET and SPECT

LOW Pgp

HIGH Pgp

Tc-99m-Sestamibi

  • Pgp pumps b-Amyloid out of the brain across

  • the BBB. Pgp polymorphisms may be

  • an imagable risk factor for AD.


Pet spect imaging of multidrug resistance p glycoprotein

Seth Gammon

Piwnica-Worms Lab, Molecular Imaging Center

Vijay

Sharma

Funding: NIH P50, RO1, DOD


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