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Definitions: Molecular Imaging


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Title: Definitions: Molecular Imaging

High Spatial ResolutionCT, MRI, Optical, US
  • MRI Imaging
  • High Density, Internalizing Receptors
  • Transferrin receptor w. Transferrin MION
  • Optical Imaging
  • Physiologic measurements
  • Volume, flow, Hb O2
  • Fluorescent-labeled ligands
  • Ultrasound Imaging
  • Physiologic measurements
  • Targeting with a single, site-directed bubble.

The Advantage of Radionuclides for Targeted
Imaging, especially Low Density Sites (lt20 nM)
George Charles de Hevesy
  • The first to identify the radioisotope tracer
  • In 1923, he used 10.6 hour lead-212 to study the
    uptake of solutions in bean plants,
    noninvasively. Used small, non-toxic amounts
    given the sensitivity of the radioactivity
  • The first experiment in animals used Bi-210 to
    label and follow the circulation of Bi-containing
    antisyphilitic drugs in rabbits.
  • In a later book with Fritz Paneth, the tracer
    method was introduced as the use of radioelements
    as indicators.

  • The first practical application of a radioisotope
    was made by George de Hevesy in 1911.
  • He suspected that meals that appeared regularly
    might be made from leftovers.
  • To confirm these suspicions de Hevesy put a small
    amount of radioactive material into the remains
    of a meal.
  • When the same meal was served, it was radioactive!

History has forgotten the landlady, but George de
Hevesy went on to win the Nobel prize in 1943 and
the Atoms for Peace award in 1959.
Imaging the In Vivo Distribution of a Gamma
Emitting Radioisotope
Unprecedented Progress
  • 1937 Discovery of the element Tc
  • 1947 Isolation of Tc-99
  • 1958 Technetium Generator
  • 1970 Instant DTPA, HSA, RBC Kits
  • 1978 Crystal structures of potential Tc
  • 2002-present
  • Smaller, neutral, more polar inert chelates
  • Maximal effective specific activity
  • Tc labeled molecules 300 MW

1934 photo of Livingston and Lawrence with the
27 cyclotron at LBL
In 1938, Glenn Seaborg and Emilio Segre
discovered Technetium-99m.
Walter Tucker Powell Richards
Mechanism TcO4- stannous ion reduced Tc
chelating agent or particle final product
Kit components stannous salt (reducing agent)
chelating agent or particle
RS-123IIQNB on 5/11/83
Market Analysis and Future Prospects
  • U.S. sales of diagnostic radiopharmaceuticals
    reached 1.53 billion in 2004 and are expected to
    rise to 3.20 billion by 2010.
  • This growth will be based on introduction of new
    products, strong demand for cardiology procedures
    and increased sales of oncology products,
    particularly FDG for PET imaging.
  • Nuclear cardiology sales of 1.06 billion in 2004
    will increase to 1.89 billion by 2010.
  • FDG sales for oncology as well as cardiology and
    neurology will increase from 249 million in 2004
    to 522 million by 2010.
  • In addition, new PET radiopharmaceuticals in the
    pipeline for specialized applications should add
    to these sales estimates.

Market Analysis and Future Prospects
  • U.S. sales of therapeutic radiopharmaceuticals
    were still on the threshold in 2005, with total
    sales of 57 million.
  • Rapid growth is anticipated over the next 5-6
    years. By 2012, therapeutic product sales should
    reach 1.9 billion, with high continuing growth
    beyond that time.
  • This will be based on the introduction of new
    therapeutic radiopharmaceuticals for treating
    lymphoma, colon cancer, lung cancer, prostate
    cancer, bone cancer and other persistent cancers.
    These agents will be used in conjunction with
    traditional therapies, enhancing their
    effectiveness, with better specificity and
    reduced side effects. Individualized Medicine!

DEVELOPMENT OF Enzyme/Receptor Targeting in humans
  • 1977 18FFDG
  • 1983 11CN-MeSpip 123IIQNB
  • 1984 18FCyclofoxy
  • 1985 11CRaclopride 99mTcNGA
  • 1985 11CCarfentanil
  • 1985 11CFlumazenil

How many radiotracers have changed clinical
care? How many have been used in combination with
The Principle of PET Coincidence Detection of
Two 511 KeV Gamma Rays is Used to Determine the
  • T1/2 (min) E? (kev) Nuclear Reaction
  • 82Rb 1.3 3350 82Sr generator
  • 11C 20 960 14N (p,?) w. 6 ppm O2
  • 13N 10 1190 16O (p,?)
  • 15O 2.05 1720 14N (d,n) w. 2 O2
  • 18F 109.6 635 20Ne (d,?) w. 0.5F2
  • 18F 109.6 635 18O (p,n)
  • 76Br 966 3980 75As (a,3n)
  • 64Cu 762 571 64Ni (p,n)
  • 124I 5976 2134 124Te (p,n)

FDG1976 to 2002
Imaging Saturable Sites with MRI
  • Relatively High Capacity, Internalizing Sites.
  • Mion-Transferrin
  • Substrates For Enzymes.
  • FDG
  • High Capacity, Non-internalizing Binding Sites.
  • A Gd complex of polyDTPA polyneogalactosyl
  • Low Capacity, Non-internalizing Binding Sites.
  • Gd antibodies targeted to solid tumors.
  • Gd labeled antibodies targeted to endothelial

In Vivo MR Imaging MR image of a mouse with TfR
and TfR- flank tumors
(a) The T1-weighted coronal SE image (3.5 min
0.3x0.3x3 mm3 resolution). TfR- tumors (right
arrowhead) and TfR tumors (left arrowhead) have
similar signal intensity. (b) Corresponding
T2-weighted gradient echo image showing
significant difference (8 min same resolution).
TfR-mediated cellular accumulation of the
superparamagnetic probe decreases signal
intensity as expected using T2- and T2-weighted
imaging pulse sequences on cellular
internalization. (c) Composite of a T1-weighted
spin echo image obtained for anatomic detail with
superimposed R2 changes after Tf-MION
administration displayed in a color map.
Other Imaging Modalities for desialylated
glycoproteins binding to the high capacity (500
nM) hepatic binding protein
Post-injection 3.8 min Liver 66 Enhancement
How can targeted imaging accelerate drug
  • William C Eckelman PhD
  • Bethesda MD

Definitions Molecular Imaging
  • The term molecular imaging can be broadly defined
    as the in vivo characterization and measurement
    of biologic processes at the cellular and
    molecular level. Weissleder Mahmood, Radiology
  • MI techniques directly or indirectly monitor and
    record the spatiotemporal distribution of
    molecular or cellular processes for biochemical,
    biologic, diagnostic, or therapeutic applications
    Thakur Lentle, Radiology 2005.

Targeting ProteinsThe Magic Bullet
  • Paul Ehrlich used the English expression magic
    bullet for the first time in his Harben
    Lectures. The German word Zauberkugel appears
    earlier in his thoughts and publications, based
    on his view of sidechains, the precursor of our
    concept of receptors, and on the desirable
    property of drugs that must not harm the host,
    but attach the parasitic invader.
  • Royal Institute of Public Health (LondonLewis,
    1908), Experimental Researches on Specific
    therapy. On immunity with special references to
    the relationship between distribution and action
    of antigens, 107.

The Magic Bullet
  • Ehrlichs first magic bullet was Salvarsan or
    arsphenamine, discovered in 1909, which provided
    the only cure for syphilis.
  • Ehrlich also thought of attaching toxins to
    antibodies whereby the antibody would carry the
    deadly freight to the site of the invading
    parasite. His idea lives on in the development of

Both the lock and the key are necessary in
Targeted Imaging
  • 99mTcDTPA or GdDTPA in GFR measurements is a key
    without a specific target (lock). GFR is a
    nontargeted process.
  • 18FFP-TZTP is a M2 muscarinic agonist, which is
    transported non specifically across the BBB, but
    binds specifically to the M2 receptor (the lock).
  • Doxorubicin in liposomes is not a targeted drug
    although the therapeutic effect is increased by
    improvement in liver tox profile.

Emil Fischer, 1894
Imaging Molecular Targeting
  • Interactions between a probe and a protein target
    using pre-genomic techniques.
  • Biochemical probes such as iodide (50 years),
    receptor binding radiotracers and monoclonal
    antibodies (25 years) from autopsy, linkage and
    drug efficacy, etc.
  • Interactions between a probe and a protein target
    using post-genomic techniques.
  • Molecular biology, proteomics, genomics,
    antisense, reporter genes, protein-protein
    interactions. More targets (500 2000-3000)

Why is Targeted Imaging becoming more important
in Drug Development?
  • As the pharmaceutical industry turns to targeted
    drugs, targeted imaging is well positioned to
    biomark the drug potential.
  • Target identification is dependent upon clinical
    research, i.e., humanomics should be the study
    of choice.

Lindsay MA. Finding new drug targets in the 21st
century. DDT 2005 23/24 1683.
The Druggable genome
Nucl Horm R
Russ Lampel. The Druggable genone an update.
DDT 2005 23/24 1607.
Measuring Targeting with Imaging for targets of
differing density
  • In Vitro B/F Bmax/Ki
  • Imaging requires B/F ratio 5, Drugs do not

Measuring the In Vivo Binding Parameters of
18F-Fallypride in Monkeys Using a PET
Multiple-Injection Protocol.
Mukherjee 2005
Measuring occupancywith Imaging for a
successful treatment
Specific binding of 18FCyclofoxy was lower by
29 to 32 in Methadone Maintained Patients.
Normal Control
Methadone Maintained Patient
Thalamus 32   15 Amygdala 24 
 30 Caudate 24   19 Ant. cingulate cortex
29   20
Kling et al., J Pharm Exp Therap, 295
1070-1076, 2000
Measuring Occupancy with Imaging for
Multi-target drugs
  • A single target drug with a multi-target
  • A multi-target drug with a single target

M100907 as measured using 11CNMSP PET in humans
  • Measure possible 5-HT2A receptor occupancy by
    measuring frontal cortex to cerebellum ratio.
  • Measure possible D2 receptor occupancy by
    measuring striatum to cerebellum ratio.
  • Is the Occupancy related to plasma concentration?
  • Is the Occupancy time course related to plasma

11CNMSP Binding at 5-HT2A D2 receptors
Schizophrenia and Antipsychotic Drugs
  • M100907 (aka MDL 100907) is a potent and
    selective 5-HT2A receptor antagonist, but does
    not bind to the D2 receptor.
  • Therefore, it has the profile of an atypical
    antipsychotic agent.
  • 11CNMSP can be used to monitor 5-HT2A and D2
    receptor density changes.

J Clin Pharmacol Suppl 1999
Sensitivity/Identifiabilityfor Drug Changes
  • Measuring endogenous transmitter changes

Measuring increased dopamine.22.3 (2.7) in
schizophrenia vs. 15.5 (1.8) in
controls.Schizophrenia is associated with
elevated amphetamine-induced synaptic dopamine.
Breier A, Su TP, Saunders R, Carson RE, Kolachana
BS, de Bartolomeis A, Weinberger DR, Weisenfeld
N, Malhotra AK, Eckelman WC, Pickar D. Proc Natl
Acad Sci U S A. 1997 Mar 1894(6)2569-74.
Measuring increased acetylcholine. 18FFP-TZTP
as a probe for AChE inhibitors such as donepezil,
rivastigmine, tacrine. Increased ACh and 15
decrease of 18FFP-TZTP in Ctx.
Carson RE, Kiesewetter DO, Jagoda E, Der MG,
Herscovitch P, Eckelman WC. Muscarinic with
18FFP-TZTP control and competition studies. J
Cereb Blood Flow Metab. 1998 Oct18(10)1130-42.
Individualized Medicine
Current Individualized Medicine
  • Metastatic pheochromocytoma (Pheo) can be
    detected using 123IMIBG (or it that is not
    available 131IMIBG can be used) prior to
    therapy with 131IMIBG.
  • The mechanism of localization is based on the
    neuroendocrine character of this disease with the
    the norepinephrine transporter (NET) being the
    key biochemical parameter.
  • Up to 73 of PHEO cells in vitro express
    somatostatin receptors so patients with Pheo have
    been assessed with somatostatin receptor imaging
    (with either 123ITyr3-octreotide or
  • Since the presence of NET and SSR appear to be
    inversely related and dependent on cell
    differentiation, imaging both pathways can be
    instrumental in choosing therapy.

Current Individualized Medicine
  • The American College of Radiology has recently
    set practice guidelines for 90Yibritumomab
    tiuxetan (Zevalin) and 131Itositumomab
    (Bexxar), which are approved by the FDA for
    radioimmunotherapy of non-Hodgkins lymphoma.
  • Both antibodies are directed against the CD20
    antigen, which is found on the surface of normal
    and malignant B lymphocytes.
  • The preliminary imaging studies are to determine
    dosimetry or assess biodistribution before the
    radiotherapeutic is administered. The package
    insert for these two radiotherapeutics has
    guidelines for interpreting the imaging study and
    these guidelines must be met before the therapy
    can commence.

Targeted Drugs Targeted Imaging
  • Trastuzumab for HER2 (aka ErbB2 Neu)
  • A cell surface glycoprotein with TK activity
  • HER2 amplification/over-expression is predictive
    for response in breast caner.
  • Overexpression became an entry criteria and
    higher objective response was related to level of
  • Imaging study was developed with Ab fragment to
    match the Ga-68 half life.

tra STUH zoo mab Herceptin
Imaging HER2 Receptor in response to HSp90
  • 17-allylaminogeldanamycin (17-AAG) is the first
    Hsp90 inhibitor to be tested in a clinical trial.
  • Induce proteasomal degradation of HER2 by binding
    to Hsp90 chaperone protein.
  • Label the F(ab)2 of the anti-HER2 antibody
    Herceptin with Ga-68.

Smith-Jones et al. Nat Biotech 2004
MicroPET images (coronal) of mice with BT-474
tumors with Ga-68-DOTAcHF at 3 h before and 24 h
after 17-AAG
Tumor kidney
Taken from Smith-Jones et al. Imaging the
pharmacodynamics of HER2 degradation in response
to Hsp90 inhibitors. Nat Biotechnol.
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Targeted Drugs
  • Imatinib is an inhibitor of BCR-ABL TK.
  • The Philadelphia chromosome and BCR-ABL have
    prognostic significance for chronic myeloid
    leukemia (CML).
  • Also, inhibits TK of the oncogene c-KIT in GIST.
  • Imatinib-resistant mutants led to BMS 354825.

im MA ta nib Gleevec
In Vivo ProteomicsFDG Before and after Gleevec
Taken from Demetri et al.
Cancer is not a single gene disease, yet ..
  • Imatinib (Gleevec)-effective in GIST and CML.
    Mutants appeared, but further TK inhibitors have
    high affinity for all mutants.
  • Trastuzumab (Herceptin)-best in high expressors
    of HER2.
  • Gefitinib (Iressa)-EGFR TK.
  • Shrinks tumor, but no change in survival in
    NSCLC. Population specific.
  • Erlotinib (Tarceva) Cetuximab (Erbitux)-MAb
  • Angiogenesis Inhibitors

DDT 200491042-1044
Golsteyn RM. DDT 2005 10(6)381.
Drivers for Targeted Imaging
  • Expansion of SPECT/CT complementing the continued
    expansion of PET/CT.
  • Development of the parallel field of small animal
  • The pharmaceutical companys need to increase
    their success rate from 17 for established
    targets and 3 for post-genomic targets.
  • The FDAs need to encourage biomarker
    development, especially for human use.

Magnitude of the opportunities
  • Failures in Phase II or Phase III are often due
    to newly identified toxicity or absence of
  • 2000 drugs have failed to target sufficiently and
    are accumulating at a rate of 150-200 per year.

Percentage of success
Arth CV CNS Inf Oncol Eye Metab
Uro Women ALL
Kola Landis Nat Rev DD 20043711-716
Efficient Molecular Targeting Discovery
  • Streamlining drug discovery finding the right
    drug against the right target to treat the right
  • For Targeted Imaging probes finding the right
    molecular probe against the right target to
    monitor the right disease.

Molecular Probe Design
  • Develop Molecular Imaging Probes that target a
    protein that changes early in the disease.
  • Develop molecular tracers that are based on a
    reductionist concept where the drug-organism
    interplay can be reduced to a drug-target
  • Collaborate with or join the Pharmaceutical

  • University Faculty
  • Chemistry dept
  • Pharmacology dept
  • Radiology dept
  • Radiopharmaceutical companies
  • Pharmaceutical companies
  • Drug development using imaging

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Target-based drug discovery Is something wrong?
  • Physiologic targets
  • For example, blood pressure measurements in vivo
    using potential drugs, e.g., the ACE inhibitors.
  • Targeted Drugs
  • Gene Targets, e.g., single gene disease
  • Mechanistic Targets (receptors, enzymes)
  • Combitorial chemisty, HTS, rationale drug
  • Underestimation of the complexity of the
    physiology and lack of relevant disease model.
  • Targeted Imaging could play a major role.

Sams-Dodd, DDT 200510139
Other Imaging Modalities for desialylated
glycoproteins binding to the high capacity (500
nM) hepatic binding protein
Mattrey, Hall Vera UCSD
Post-injection 3.8 min Liver 66 Enhancement
Comparison of HER2 status between primary tumor
and disseminated tumor cells in primary breast
cancer patients.
  • RESULTS In 46 of 137 (34) breast cancer
    patients, CK-positive cells were detectable in
    BM. DTC with HER2 positivity were found in 20
    (43) of these patients.
  • The HER2 expression on DTC was heterogeneous in 7
    of 17 (41) patients.
  • Concordance rate of HER2 status between primary
    tumor and DTC was 62. In 12 of 20 patients with
    HER2 negative tumors HER2 positive DTC were
  • HER2 positive DTC can be detected in patients
    with HER2 negative primary tumors.

Solomayer EF et al. Breast Cancer Res Treat. 2006
Mar 22 Epub ahead of print
HER2-positive circulating tumor cells (CTC)
indicate poor clinical outcome in stage I to III
breast cancer patients.
  • We detected one to eight CTCs in the peripheral
    blood of 17 of 35 patients (48.6) presenting no
    overt metastasis.
  • As a positive control, 7 of 7 (100) patients
    with metastatic disease presented positive.
  • The presence and frequency of HER2-positive CTCs
    correlated with a significantly decreased
    disease-free survival (P lt 0.005) and overall
    survival (P lt 0.05).
  • Interestingly, in 12 patients with HER2-positive
    CTCs, the primary tumor was negative for HER2 as
    assessed by immunohistochemical score and
    fluorescence in situ hybridization.
  • This study provides some evidence of a prognostic
    effect of HER2-positive CTCs in stage I to III
    breast cancer.

Wulfing P et al. Clin Cancer Res. 2006 Mar
Predictive Factors for Outcome in a Phase II
Study of Gefitinib in Second-Line Treatment of
Advanced Esophageal Cancer Patients.
  • Gefitinib has a modest activity in second-line
    treatment of advanced esophageal cancer.
  • However, the patient outcome was significantly
    better in female patients and in patients
    demonstrating high EGFR expression or SCC
  • The selection of esophageal cancer patients for
    future studies with EGFR-TKIs based on the level
    of EGFR expression in their tumors or SCC
    histology should be considered.

Janmaat ML et al. J Clin Oncol. 2006 Apr
What makes a probe a targeted molecule?
  • Does the probe bind to the target?
  • If there are a limited number of sites, increased
    mass should decrease probe binding.
  • Is the delivery dependent on flow, permeability,
    or protein concentration?
  • What does flow dependence look like?
  • What does permeability dependence look?
  • Is the probe sensitive to target change?

Epidermal growth factor receptor inhibitors in
cancer treatment.
  • The epidermal growth factor receptor (EGFR) is a
    cellular transmembrane receptor with tyrosine
    kinase enzymatic activity which plays a key role
    in human cancer. EGFR-dependent signaling is
    involved in cancer cell proliferation, apoptosis,
    angiogenesis, invasion and metastasis.
  • Cetuximab (Erbitux(R)), a chimeric human-mouse
    monoclonal immunoglobin (Ig)G(1) antibody, which
    blocks ligand binding and functional activation
    of the EGFR, is currently registered in the USA,
    Switzerland and the European Union for the
    treatment of advanced, irinotecan-refractory
    colorectal cancer. Gefitinib, (Iressa((R))), a
    small molecule EGFR-selective inhibitor of
    tyrosine kinase activity which blocks EGF
    autophosphorylation and activation, has been the
    first EGFR-targeting drug to be registered in 28
    countries worldwide, including the USA, for the
    third-line treatment of chemoresistant non-small
    cell lung cancer patients.

Ciardiello F. Future Oncol. 2005
Antiangiogenic cancer therapies get their act
together current developments and future
prospects of growth factor- and growth factor
receptor-targeted approaches
  • The identification of surrogate markers that can
    monitor the activity and efficacy of
    antiangiogenic drugs in patients belongs to the
    most critical challenges to exploit the full
    potential of antiangiogenic therapies. The
    opportunities and obstacles in further
    development of growth factor- and growth factor
    receptor-targeted antiangiogenic approaches for
    advanced cancer, including malignant melanoma,
    will be discussed herein with particular
    reference to selected ongoing clinical trials.

Gille J. Exp Dermatol. 2006 Mar15(3)175-86.
Triage for Breast Cancer
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