Epidemiology of Back Pain

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What is Molecular Imaging?
Radiological Society of North America Molecular
Imaging Refresher Course Chicago, IL
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The evolution of diagnostic imaging
PAST PRESENT
FUTURE
Molecular NM, PET, SPECT, MRS, optical,
PET/MRI contrast-enhanced MRI/US/CT
Hybrid PET/CT, SPECT/CT, PET/MR
Functional angiography, doppler US, NM, MRI,
PET
Anatomic plain films, CT, MRI, US
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Molecular imaging definition

• The remote sensing of cellular processes at the
  molecular level in vivo.

• Molecular Imaging is the noninvasive
  visualization in space and time of
• cellular processes at a molecular or genetic
  level of function. It is used
• to provide characterization and measurement of
  biological processes
• in living animals and humans.

• MI techniques directly or indirectly monitor and
  record the spatiotemporal
• distribution molecular or cellular processes for
  biochemical, biologic, diagnostic,
• or therapeutic applications.

• Molecular Imaging is the non-invasive imaging of
  molecular/cellular
• events in living organisms to study biological
  processes and to diagnose
• and manage diseases.

• Molecular Imaging is a procedure performed by
  using any imaging device to monitor and record
  molecular or cellular interactions in biological
  processes for biochemical, diagnostic or
  therapeutic applications.

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Molecular imaging definition

• Molecular imaging is the visualization,
  characterization, and measurement of biological
  processes at the molecular and cellular levels
  in humans and other living systems.

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Molecular imaging goals

• develop new imaging probes and technologies
• facilitate new drug development and methods
  for therapeutic monitoring
• image gene delivery and expression
• understand cellular processes in their intact
  microenvironments

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Utility of molecular imaging for clinical medicine

• early detection of changes occurring in tissue
• enables changes in individual patient
  management in real time (personalized medicine)
• facilitates drug development

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HIV brain infection
(Microbes Infect 2002 4301)
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Molecular imaging modalities
Sensitivity
Modality Agents H R Primary uses Examples
FMT fluorescent proteins x X gene expression, tagging superficial structures GFP, RFP, NIRF probes
BLI luciferin X gene expression, therapeutic monitoring fLuc rLuc
pM
SPECT 99mTc, 123/5I, 111In X X site-selectivity, protein labeling 99mTc-annex in V, 123I-A85380
PET 11C, 18F, 124I, 64/62/60Cu X X site-selectivity, gene expression, drug development 11C-RAC, 124I-FIAU, 64Cu-ATSM
nM
spectro-scopy endogenous metabolites X X CNS, prostate , heart , breast NAA, Cr, Cho, Glx, mI, 31P
contrast agents Gd, Mn, FeO x X cell trafficking, enzymatic activation poly-L-lysine, dendrimers, MION
mM
contrast agents perfluorinated microbubbles X drug-delivery, gene transfection human albumin (Optison)
one mbubble
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Positron emission tomography PET


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Why radionuclide techniques translate
readily the tracer principle

• Give 5 mCi of 5,000 Ci/mmol 11Ccarfentanil
  (m opioid receptor ligand) to a 70 kg individual
  5.5 x 10-6 mg/kg mass dose

• 2.5 mg/kg IM is used to immobilize elephants

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Molecular imaging goals

• develop new imaging probes and technologies
• facilitate new drug development and methods
  for therapeutic monitoring
• image gene delivery and expression
• understand cellular processes in their intact
  microenvironments

• new imaging probes

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Prostate cancer why image?

• one man dies of hormone-refractory disease
  every 20 min. in US alone
• clinical understaging in 25 of men who have
  undergone radical prostatectomy
• PSA in normal tissues/sampling error from
  biopsy
• to direct biopsy and/or therapy (conformal
  radiotherapy or brachytherapy)
• difficult to obtain metastatic biopsy specimens
  bone scanning lags tumor response and is not
  mechanism-based
• preoperative pelvic nodal staging
• detection of recurrence in post-prostatectomy
  patients with rising PSA

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Prostate cancer why image?

• one man dies of hormone-refractory disease
  every 20 min. in US alone
• clinical understaging in 25 of men who have
  undergone radical prostatectomy
• PSA in normal tissues/sampling error from
  biopsy
• to direct biopsy and/or therapy (conformal
  radiotherapy or brachytherapy)
• difficult to obtain metastatic biopsy specimens
  bone scanning lags tumor response and is not
  mechanism-based
• preoperative pelvic nodal staging
• detection of recurrence in post-prostatectomy
  patients with rising PSA

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SPECT imaging with ProstaScint
(Wilkinson, et al. J Urol, 2004 172133)
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PSMA overexpressed on prostate tumors and most
solid tumor neovasculature
CO2H
F
E
D
C
outside
B
inside
A
H2N
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A conventional target PSMA
A marker for prostate cancer, particularly
androgen-independent disease, and tumor
neovasculature
O
H
O
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PSMA three domains dimer
C-terminal - 591-750
protease - 57-116 and 352-590
apical - 117-351
(Courtesy Cyril Barinka)
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S1 binding pocket arginine patch
Most inhibitors have glutamate at the
P1 Virtually identical mode of glutamate
binding at the S1 Diverse moieties tolerated at
the P1 position
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11CDCMC radiosynthesis
45oC, 3 min 12 non-decay
11CDCMC gt 150 GBq/mmol
a direct probe for PSMA
(Mol Imaging 2002 196)
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ATLAS PET imaging of PSMA with 11CDCMC
LNCaP
(Foss et al., Clin Cancer Res, 2005 114022)
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Urea-based PSMA inhibitors 18FDCFBC
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Mouse whole body pseudo-dynamic scan
Time-Activity-Curves
9 cm
23 g mouse, 300 mCi 18F-labeled tracer, tumor on
left side Whole body scans, 2 beds _at_ 5 min each,
4 slices overlap, repeated multiple
times Reconstruction FORE/2D-OSEM with 2
iterations, 16 subsets
Dwell time per bed position can be shortened!
(Jurgen Seidel)
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Urea chelates
PIP
FLU
(Sangeeta Ray Banerjee and Catherine Foss)
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Urea chelates
PIP
FLU
(Sangeeta Ray Banerjee and Catherine Foss)
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Molecular imaging goals

• develop new imaging probes and technologies
• facilitate new drug development and methods
  for therapeutic monitoring
• image gene delivery and expression
• understand cellular processes in their intact
  microenvironments

• molecular-genetic imaging

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Needed reporter gene/reporter probe system for
imaging signal transduction
gli
(125IFIAU)
HSV thymidine kinase
indirect imaging

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Signal amplification utility of enzymatic
reporters
D2DR
HSV1-TK
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Unconventional target hedgehog signaling
cascade
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Multimodality imaging of the hedgehog signaling
cascade in experimental brain tumors
(Zhang et al., Soc. Mol. Im. 2005)
Vector backbone courtesy S. Sam Gambhir
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Bioluminescence imaging of the hedgehog signaling
cascade in experimental brain tumors
BLI
BLI U87 cells were transfected with
Gli-trireporter, and injected into nude mice at
left and right shoulders. Tumors generated were
imaged with the Xenogen IVIS 200 optical imaging
system. Left mouse injected with wt U87 cells.
Right mouse injected with U87-Gli-tri cells.
(Zhang et al., Soc. Mol. Im. 2005)
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Molecular imaging goals

• develop new imaging probes and technologies
• facilitate new drug development and methods
  for therapeutic monitoring
• image gene delivery and expression
• understand cellular processes in their intact
  microenvironments

• clinical translation

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Heterogeneous oxygenation of tumors
anaerobes home to the hypoxic core and
proliferate bacteriolytic therapy
(Chetan Bettegowda)
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Bacterial strains tested
Bifidobacteria ATCC Number B. adolescentis ATCC
15703 B. animalis ATCC 25527 B. bifidum ATCC
11863, 15696 B. boum ATCC 27917 B. breve ATCC
15700 B. coryneforme ATCC 25911 B.
dentium ATCC 15423, 27534 B. indicum ATCC
25912 B. infantis ATCC 15702, 25962 B.
longum ATCC 15707 B. magnum ATCC 27540 B.
pseudolongum ATCC 25526   Lactobacilli L.
bifidus ATCC 11146 L. delbruecki ATCC
21815 Clostridia C. absonum ATCC 27555 C.
acetobutylicum ATCC 824 C. bifermentans ATCC
17836 C. difficile ATCC 700057 C.
histolyticum ATCC 19401
C. novyi (type A) ATCC 19402
C. novyi (type A) ATCC 19402 C. sordellii ATCC
9714 C. perfringens ATCC 3624, 13124
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Effects of C.novyi in vivo
Gram Stain

• Wild type C. novyi lethal in mice
• C. novyi lethal toxin was inactivated to yield
  C. novyi-NT

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Clinical need to image the bacteria as they
home in on tumors

• Do we need to transfect the bacteria with a
• reporter gene/reporter probe?

Labeled
Reporter
reporter probe
gene/
HSVtk
Phosphorylated
Reporter enzyme
promoter
probe trapped in
HSV
thymidine
kinase
the cell
NO
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Bacteriolytic therapy potential for molecular
imaging
If bacteria can be killed by FIAU, they can be
imaged by 125IFIAU.
(Chetan Bettegowda)
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Tumors can be imaged with radiolabeled FIAU, once
bacteria have homed to them
tumor C. novyi-NT tumor C. novyi-NT
125IFIAU
(Bettegowda et al., PNAS 2005 1021145)
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Mechanism of FIAU Uptake

• To test whether thymidine kinase mediates
  sensitivity to FIAU,
• TK null E. coli were generated

(Bettegowda et al., PNAS 2005 1021145)
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Mechanism-based bacterial imaging infected
prosthetic joints
Uniform criteria have not been established for
the diagnosis of infection associated with
prosthetic joints. - New England Journal of
Medicine, October 14, 2004
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(Diaz et al., PLoS One, 2007 2e1007)
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MR Tracking of Magnetically Labeled Stem Cells

• Stem cells constitute natures repair shop
  and have shown nearly unlimited therapeutic
  potential in animal models following
  transplantation

• Unlike pre-clinical studies, the use of stem
  cells in humans will require a non-invasive
  technique to determine their fate following
  grafting

(Courtesy Jeff Bulte)
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Stereotactic transplantation
Brain biopsy
Cell migration
1-2 wks
Isolate stem cells
Remyelination
Generate myelinating cells
48 h
Add magnetic label
(Courtesy Jeff Bulte)
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MION-46L-OX26
Transferrin Receptor-Mediated Endocytosis
(Courtesy Jeff Bulte)
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Application to Use of Neural Stem Cells 3D MR
Tracking of Magnetically Labeled
Oligodendrocyte Progenitors in Rat Spinal Cord
5.0 mm

• These cells fully retain their
  myelinating capacity in vivo

New Myelin
(Courtesy Jeff Bulte)
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What is molecular imaging?
Measuring the concentration of NAA in the
brain of a patient with ALD
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What is molecular imaging?
Measuring the concentration of NAA in the
brain of a patient with ALD
YES MR spectroscopy
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What is molecular imaging?
Using CT to calculate the permeability x surface
area in a brain tumor
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What is molecular imaging?
Using CT to calculate the permeability x surface
area in a brain tumor
NO CT (or MR) perfusion
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What is molecular imaging?
Demonstrating decreased fractional anisotropy in
the posterior limb of the internal capsule in
patients with ALS
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What is molecular imaging?
Demonstrating decreased fractional anisotropy in
the posterior limb of the internal capsule in
patients with ALS
NO diffusion tensor imaging
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What is molecular imaging?
Proving that no eloquent cortex will be
removed during surgery for an anaplastic
astrocytoma
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What is molecular imaging?
Proving that no eloquent cortex will be
removed during surgery for an anaplastic
astrocytoma
NO functional MR imaging
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What is molecular imaging?
Using the BOLD MR signal to differentiate the
stereoisomers of ketamine in the rat
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What is molecular imaging?
Using the BOLD MR signal to differentiate the
stereoisomers of ketamine in the rat
MAYBE pharmacologic MR