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Aug 1, 2011 (Vol. 31, No. 14)

Imaging Secures Development Role

Early Integration May Speed Progression of Drug Candidates through Pipeline

  • Molecular imaging is broadly defined by the Society of Nuclear Medicine as “the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in humans and other living systems.” It is used extensively in drug discovery and development, for diagnosis and to monitor the efficacy of therapies.

    With so many modalities, from CT and PET to ultrasound and MRI and compounds, from radiolabeled pharmaceuticals to fluorescently labeled small molecules to dense contrast agents and players in the field, it was inevitable that “In Vivo Molecular Imaging in Drug Discovery and Development” would draw a diverse slate of speakers. The June meeting brought those working on the physics and chemistry of probe construction together with clinician-scientists, to discuss current issues in and future directions of the field.

  • Details on Efforts to Standardize Molecular Imaging Usage, Data Acquisition, and Data Interpretation

    The range of techniques, agents, and stakeholders involved in molecular imaging creates variations in imaging results. Reasons for poor quality include:

    • Lack of proper clinical design
    • Difference in how PET scans are done
    • Variations in equipment
    • Varying expertise and experience of the readers

    Through its Clinical Trials Network, the Society of Nuclear Medicine is working to forge order out of all that chaos. Click here for more.

  • A common theme among the conference's participants is that development of molecular imaging agents should start early in the drug development process. According to Juri Gelovani, M.D., Ph.D., president of the Academy of Molecular Imaging, this should happen as soon as a clinical target is locked in, perhaps even preceding development of the therapeutic itself.

    Whether it's measuring target expression levels or levels of receptor occupancy and determining pharmacodynamics or pharmacokinetics, the effects of biological approaches need to be validated in parallel to drug development in order to allow for timely transition into the clinics, concurred Thomas Krucker, head of molecular imaging for the global imaging group at Novartis Institutes for BioMedical Research. Co-development of the drug and diagnostic together would save time and resources.

    Molecular imaging should be integrated with the drug discovery project teams, rather than run like a core service. At Novartis, he said, they develop customized solutions that use imaging to seek information that can't be found through other technologies.

    Labeled biopharmaceuticals are an obvious source for imaging agents, Krucker said. Yet many biologicals display properties such as slow clearance and low target to background ratios, and because of their large size they may suffer from low stability or poor tissue penetration as well, making them less than ideal for the purpose. These issues can sometimes be addressed by engineering the proteins into smaller formats, for example Fab fragments or diabodies, instead of intact monoclonal antibodies.

    Imaging agents, as compared to doses of therapeutic agents, are administered in very low amounts that don't induce pharmacologic effects, added Dr. Gelovani. They should provide quantitative information about the spatial distribution and magnitude of drug-target expression and activity in tumors as well as other normal organs and tissues.

  • Imaging Therapeutics

    Click Image To Enlarge +
    Researchers at Queen Mary University are using a variety of preclinical imaging modalities to optimize compounds destined to become pharmaceuticals. A SPECT image of the uptake of a radiolabelled peptide by a tumor (on the right) and kidneys overlaid on a CT scan of the mouse skeleton is shown.

    Of course, sometimes the imaging agent should be as similar to the therapeutic agent as possible—especially if the goal is to track the therapeutic agent itself.

    Stephen Mather, Ph.D., professor at Barts Cancer Institute, Queen Mary University of London, has been concentrating his efforts on using a variety of preclinical imaging modalities to optimize compounds destined to become pharmaceuticals. His presentation, sponsored by BioScan, focused on research using that company's dual-mode NanoSPECT/CT system.

    In vivo preclinical imaging in animal models, he said, can help to identify much earlier in the process whether a drug is likely to ultimately be successful in patients.

    His lab collaborates with GlaxoSmith-Kline on a project to target interferon (IFN) to the liver. IFN is known to be effective against hepatitis C infection, but because its receptors are present throughout the body, systemic delivery results in considerable side effects including hallucinations.

    The researchers conjugated IFN to an antibody against the asialoglycoprotein receptor, which “is pretty much only present on liver cells,” Dr. Mather said. They then radiolabeled the bi-specific compound. “We've shown quite convincingly that by tagging the IFN onto the antibody, you do get much more of the drug in the liver rather than elsewhere.”

    They also collaborate with several other academic labs across Europe in a program sponsored by the EU's Cooperation in Science and Technology program. The study compared which of nine different radiolabeled peptides seemed to best target a receptor found on medullary thyroid cancer. “This allows just one compound to be taken forward into clinical trials, which are increasingly difficult and expensive to do,” Dr. Mather explained.

  • Click Image To Enlarge +
    In vitro autoradiography (competition binding) shows receptor localization with the radioligand alone (A) and receptor upregulation in the prefrontal cortex and hippocampus with the addition of an alpha-7 agonist (B). MLA inhibition of the radioligand is the positive control (C). [Jennifer Werkheiser, Ph.D., BrainCells/AstraZeneca]

    Following a traditional screening cascade from recombinant and native tissue to autoradiography to an in vivo radioimaging model, is very helpful in understanding whether something is potentially suitable as an in vivo PET radio tracer, said Donna Maier, Ph.D., who recently joined BrainCells. It's invaluable for exploring novel radioligands, and “it's also important for validating within your own lab, potentially for the first time, a radioligand that's available commercially.”

    While in the molecular imaging group at AstraZeneca, Dr. Maier's team worked on the a-7 neuronal nicotinic receptor (NNR)—an important target for psychiatric and cognitive disorders such as schizophrenia and Alzheimer disease. They would pretreat an animal with a drug compound before administering a radiolabeled ligand, and then dissect the brain at various time points.

    Inhibition of the radioligand binding would imply that the drug is occupying the receptor. In this way, they were able to rank-order compounds to pursue further in PET studies. “It's a competition assay, but it's in vivo.”

    When one particular ligand was used, they found what seemed to be a paradoxical decrease in receptor occupancy by the microgram dose of the pretreatment compound, in which there were more receptors available for radioligand binding. “You're actually increasing the receptor density at the neuron and you're increasing the binding of the radioligand—and so it results in a mathematically negative receptor occupancy,” Dr. Maier explained.

    Some behavioral assays indicated that the animals may actually be more sensitive to less compound. Taken together, these studies “may indicate that you're looking at nontraditional dosing regimens as you translate preclinical data to clinical studies and try to administer this type of compound to humans,” she said. “We found an interesting way to utilize molecular imaging and try to further understand our compounds.”

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