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    Jan 28-29

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    Sheila Kwok
    This document discusses molecular imaging techniques using radiopharmaceuticals. It describes various imaging modalities like PET and different radioactive tracers used. Positron emission tomography (PET) tracers are often radiolabeled small molecules or antibodies. Tracers are developed by labeling them with radioactive isotopes like fluorine-18 at a radiosynthesis lab using automated synthesizers. Preclinical testing involves imaging immunocompromised animals and validating targets. Examples discussed are gallium-68 labeled DOTATATE for imaging neuroendocrine tumors and targeting mitochondrial metabolism in cancers. The document also outlines strategies for radiolabeling antibodies and developing pretargeted imaging probes.

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    Jan 28-29

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    Sheila Kwok
    31 views42 pages
    This document discusses molecular imaging techniques using radiopharmaceuticals. It describes various imaging modalities like PET and different radioactive tracers used. Positron emission tomography (PET) tracers are often radiolabeled small molecules or antibodies. Tracers are developed by labeling them with radioactive isotopes like fluorine-18 at a radiosynthesis lab using automated synthesizers. Preclinical testing involves imaging immunocompromised animals and validating targets. Examples discussed are gallium-68 labeled DOTATATE for imaging neuroendocrine tumors and targeting mitochondrial metabolism in cancers. The document also outlines strategies for radiolabeling antibodies and developing pretargeted imaging probes.

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    CHEMBIO 3AA3 NOTES

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    This document discusses molecular imaging techniques using radiopharmaceuticals. It describes various imaging modalities like PET and different radioactive tracers used. Positron emission tomography (PET) tracers are often radiolabeled small molecules or antibodies. Tracers are developed by labeling them with radioactive isotopes like fluorine-18 at a radiosynthesis lab using automated synthesizers. Preclinical testing involves imaging immunocompromised animals and validating targets. Examples discussed are gallium-68 labeled DOTATATE for imaging neuroendocrine tumors and targeting mitochondrial metabolism in cancers. The document also outlines strategies for radiolabeling antibodies and developing pretargeted imaging probes.

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    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    31 views42 pages

    Jan 28-29

    Uploaded by

    Sheila Kwok
    This document discusses molecular imaging techniques using radiopharmaceuticals. It describes various imaging modalities like PET and different radioactive tracers used. Positron emission tomography (PET) tracers are often radiolabeled small molecules or antibodies. Tracers are developed by labeling them with radioactive isotopes like fluorine-18 at a radiosynthesis lab using automated synthesizers. Preclinical testing involves imaging immunocompromised animals and validating targets. Examples discussed are gallium-68 labeled DOTATATE for imaging neuroendocrine tumors and targeting mitochondrial metabolism in cancers. The document also outlines strategies for radiolabeling antibodies and developing pretargeted imaging probes.

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    CB 3AA3

    Lecture 7-8 Jan 28-29, 2021


    Saman Sadeghi
    Sadegs10@mcmaster.ca
    Molecular Imaging

    MOLECULAR In vivo
    BIOLOGY Imaging
    Imaging Modalities
    Imaging Modalities
    Abnormal cells with
    pathological phenotypes

    Molecular expression

    Probes / ligands may


    be detected and allow

    Therapy
    Diagnosis with labeled
    compounds

    Identification Therapy
    of targets Therapy response
    for drugs planning
    Radiopharmaceuticals
    • A radiopharmaceutical is a drug labeled with a
    radionuclide targeting biological process
    • The overall chemical structure determines biological
    properties
    • the radionuclide determines imaging and/or
    therapeutic properties
    PET Tracer Development
    PET tracer development
    Production of positron-emitting
    radioactive isotope
    • Have to hit the target nucleus without enough
    force to overcome the binding energy
    Radioactive transformations
    Positron emission process
    • positrons travel through human tissues, they give up
    their kinetic energy mainly by Coulomb interactions
    with electrons
    • rest mass of the positron is the same as that of the
    electron => large deviations in direction with each
    Coulomb interaction, and they follow a tortuous
    path
    18F - Physical properties
    18
    9F T1/2 = 109.8 minutes

    b+ 96.73% Eb+max = 635 keV


    EC 3.27% Eg = 511 keV

    8O
    18

    Methods of preparation:
    18O ( p , n ) 18F 16O ( a, 2n ) 18F
    20Ne ( d , a ) 18F
    16O ( 3He , p ) 18F 20Ne ( 3He , ap ) 18F
    16O ( a , pn ) 18F 18F
    History of cyclotrons
    • Conceived in 1920s, first operated in 1932
    • Stanley Livingston (L) and Ernest O. Lawrence
    1934, 27 inch cyclotron
    Major Components of a cyclotron

    • Vacuum chamber
    • Ion source
    • Magnetic field and RF voltage for high energy beam generation
    • Beam extraction and proton generation
    • Target
    RADIOCHEMISTRY LAB
    • Radiosynthesis lab QC setup
    Radiosynthesis

    Radiosynthesizer Rotary
    evaporator

    Hot cell

    Semi-prep HPLC
    Automated synthesizers

    Steel et al. J Label Compd Radiopharm 50: 308-311 (2007)


    FDG, 10 min reaction, 9 sec residence time
    Hotcells and Synthesizers
    Preclinical Imaging
    Molecular Imaging

    Chemistry
    Immunocompromised Animals
    Imaging and Validation
    In vitro Studies
    68Ga-DOTATATE

    • Neuroendocrine tumors
    • Low glucose consumption but high
    expression of
    somatostatine
    receptors
    68Ga-DOTATATE

    • Relapse detection
    • In conjunction with FDG
    Theranostics

    • Targeted radionuclide therapy


    • (Ga-68-DOTATATE PET/CT) to detect the
    presence of a molecular target
    • Somatostatin receptor positive selected for
    therapeutic intervention (Lu-177-DOTATATE)
    Targeting Of Mitochondrial
    Metabolism
    • Functionally map mitochondrial
    networks in oxidative and non-
    oxidative
    • Similar metabolic signatures in
    HNSCC and Triple Negative Breast
    Cancer, going beyond FDG

    37
    Antibody and Fab radiolabeling

    Reference
    Fu, R.; et al. Antibody Fragment and Affibody ImmunoPET Imaging Agents: Radiolabelling Strategies and
    Applications. Biopolymers. 2019
    38
    Radiolabelled Antibody Recruiting Molecules

    • Form of cancer therapy that Target Binding Antibody Binding


    Terminus Terminus
    activates the immune
    system to “attack” the
    tumour
    • Using small molecules Cancer Cancer
    containing a known antigen cell cell
    to recruit endogenous Radiolabelled ARM
    antibodies to the tumour
    • Antibody - labelled cancer
    cells become “visible” to Delivery of
    cytotoxic radiation
    the immune system
    • Concentration of ARM
    required for cell death is
    similar to that required for Immune-mediated
    radiotherapy Clearance

    Spiegel et al. J Am Chem Soc. 2009, 131(47), 17090–17092


    Strategy For Radiolabeling

    Cysteine Residues Lysine Residues


    DFO-Bz-SCN DOTA-NHS

    Advantage: Site-selective Advantage: >20 available lysine


    Disadvantage: Antibody Instability Disadvantage: Can reduce affinity
    Disadvantage: Max ~8 cysteine

    40
    Pretargeted Imaging

    Fast
    Selective
    Bio-orthogonal
    Experimental Strategy

    1 Antibody Conjugation
    and Validation

    2 Radiolabelled Tetrazine
    Probe Development

    3 In vivo Testing

    42
    Strategic Overview
    Creating a Novel Radiolabelled anti-CD133 antibody

    Conjugation Radiolabelling

    Probe
    Development

    In vitro In vivo

    Evaluation

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