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PET Imaging of Small Animals: Molecules for Molecular Imaging . Department of Chemistry and the McMaster Institute of Applied Radiation Sciences With the support of : The Department of Nuclear Medicine, Hamilton Health Sciences. Molecular (Radio) Imaging.

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PET Imaging of Small Animals: Molecules for Molecular Imaging


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pet imaging of small animals molecules for molecular imaging

PET Imaging of Small Animals:Molecules for Molecular Imaging

Department of Chemistry and the McMaster Institute of Applied Radiation Sciences

With the support of :

The Department of Nuclear Medicine, Hamilton Health Sciences

molecular radio imaging
Molecular (Radio) Imaging
  • Diagnostic techniques that allow for the study of
  • specific biochemical processes
  • Can be done in vivo (SPECT, planar imaging, PET) or
  • in vitro (fluorescence, autoradiography)
  • Requires the development of radiolabeled compounds
  • (contrast agents)
radiotracers
Radiotracers
  • Compounds which carry a radionuclide whose emissions can be tracked by an external detector
    • Gamma emitters (SPECT/planar imaging)
    • Positron emitters (PET)
  • Used to follow the distribution and biochemistry of a particular compound
the tracer principle
The Tracer Principle

The amount of tracer used in a study is so small

that it does not perturb the biological system

under investigation.

areas of research
Areas of Research
  • The preparation and testing of radiopharmaceuticals and fluorescent compounds for:
    • Clinical diagnostic imaging (SPECT and PET)
    • Drug testing
    • Radiotherapy
  • Novel radiolabeling and drug discovery techniques
specifics
Specifics
  • Technetium (Tc) labeled peptides and hormones
  • Small molecule Tc complexes for molecular imaging
  • 18F labeled hormones for PET
technetium 99m 99m tc
Technetium-99m (99mTc)
  • Gives off gamma rays that can be detected by a scintillation camera
  • The most widely used radionuclide in diagnostic medicine (ideal nuclear properties, readily available, low cost)
tc essential compounds
Tc-Essential Compounds
  • “Simple” complexes-distribution determined based on charge, size, lipophilicity etc.
molecular radioimaging
Molecular Radioimaging
  • Use a biomolecule to guide 99mTc to a particular receptor
  • Requirements:
    • Bond between Tc and the biomolecule will not degrade in vivo
    • Attachment of Tc will not alter the selectivity of the parent targeting agent
bifunctional chelates
Bifunctional Chelates
  • Used to append Tc to biomolecules
  • The chelate must be able to form a Tc complex in water where the metal is in very low concentrations (10-8 M to 10-9 M)
  • All reactions begin with TcO4-
problems
Problems
  • Existing Tc ligands are large
  • Metal complexes are susceptible to premature degradation in vivo
  • Limited synthetic flexibility
project 1 develop better ligands
Project 1: Develop better ligands

Linker site

Metal binding

  • Stable
  • Prepared in high yield
  • Easily linked to targeting agents
peptides
Peptides
  • Small peptides have proven to be effective targeting agents

111In-OctreoScan

library construction
Library Construction
  • Use the automated synthesizer to prepare families of analogues in parallel
correlating in vivo and in vitro molecular imaging
Correlating in vivo and in vitro molecular imaging

Screen RBA’s in vitro and in vivo

Look for localization at the cellular level

summary
Summary
  • Prepare libraries of any peptide (up to 30 amino acids) carrying a fluorescent tag or a radiolabel
  • Correlated in vitro and in vivo imaging
  • Molecular therapy using radioactive Re-isotopes
small molecule tc radiopharmaceuticals
Small Molecule Tc Radiopharmaceuticals

Designed to image biological processes

    • Amino acid metabolism
    • Carbohydrate utilization
  • Challenge: You need a small Tc-compound that is stable in vivo and easily functionalized
functionalized carboranes
Functionalized Carboranes

Amines, amino acids

Carbohydrates

ER agonists/antagonists

molecular imaging
Molecular Imaging
  • Targeting receptors that exits in low concentrations is a real challenge
  • You must not violate the tracer principle
the excess ligand problem
The Excess Ligand Problem

Large excess

Must be removed

first year chemistry
First Year Chemistry

“Like dissolves like”, “Oil and Water don’t mix”

Polar compounds have affinity for each other

Non-polar compounds have affinity for each other

Fluorine rich compounds have affinity for each other

fluorous labeling strategy
Fluorous Labeling Strategy

R = Biomolecule

X= Radionuclide

removing the fluorous material
Removing the Fluorous Material

Solid-Phase Extraction

125 i labeling
125I Labeling

Used to tag proteins, antibodies

the fluorous labeling system
The Fluorous Labeling System
  • Rapid and “hands free” synthesis and labeling of compounds
  • Applicable to a significant number of different isotopes:
    • Iodine-123 (SPECT)
    • Iodine-125 (Therapy and animal imaging)
    • Iodine-124 (PET)
    • Fluorine-18 (PET)
    • Carbon-11 (PET)
imaging in drug development
Imaging in Drug Development
  • Look at the distribution of a labeled version of a new drug candidate
  • Study receptor specificity of new compounds (screening in vivo)
  • Evaluate different drug delivery systems
the future
The Future
  • Animal Imaging (animal PET and SPECT/CT)
  • Cancer imaging and therapy
  • Targeted MRI and CT contrast agents
acknowledgements
Acknowledgements

Syracuse University

Molecular Insight Pharma. Inc.