Infection imaging with technetium-99m-labeled chemotactic peptide analogs*

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The localization of occult sites of infection is frequently essential to the therapeutic management of critically ill patients. Current imaging procedures, including computed tomography, ultrasound, magnetic resonance imaging, and conventional radiography, rely primarily on focal changes in tissue density or composition to define the lesion. Typically, these are relatively late changes in the inflammatory process. Radionuclide procedures which have been used to localize early inflammatory processes, require a minimum of 12 hours, and usually 24 to 48 hours, from the time of injection to imaging. Clearly, a method of rapidly localizing sites of acute inflammation would be helpful for patient management. Recently, we developed methods for preparing analogs of the leukocyte chemoat-tractant peptide, N-formyl-methionyl-leucyl-phenylalanine (ForMLF), that can be radiolabeled for external imaging. In vitro, these compounds have bioactivity and neutrophil ForMLF receptor binding comparable with that of the native peptide. Studies in animals demonstrate that these agents bind to leucocytes in vivo, clear from the circulation rapidly, and localize at sites of Escherichia coli infection to an extent sufficient to yield external images early after injection. However, even at relatively low doses, the peptides elicit a profound but transient reduction in peripheral leukocyte levels. Despite this, if the peptides could be radiolabeled at very high specific activity, imaging might be possible with doses of peptide that do not reduce peripheral leukocyte levels. Recently, hydrazino nicotinamide-derivatized peptides were prepared and radiolabeled with technetium-99m at extremely high specific activity (>20,000 mCi/μmole). In a rabbit model of E coli infection, these peptides yielded excellent images of sites of infection at injected doses that are approximately 1,000-fold below the level that produces a significant reduction in peripheral leukocytes. In addition, studies of thermally injured infected animals indicate that peptide localization may be infection selective, with very low levels of accumulation at sites of sterile inflammation.

References (43)

  • Rojas-BurkeJ

    Health officials reacting to infection mishaps

    J Nucl Med

    (1992)
  • LocherJT et al.

    Imaging of inflammatory lesions after injection of radioiodinated monoclonal antigranulocyte antibodies

    Nucl Med Commun

    (1986)
  • RubinRH et al.

    111Inlabeled nonspecific immunoglobulin scanning in the detection of focal infection

    New Engl J Med

    (1989)
  • RubinRH

    In search of the hot appendix—A clinicians view on inflammation imaging

    J Nucl Med

    (1990)
  • TzenKY et al.

    Role of iron-binding proteins and enhanced vascular permeability in the accumulation of gallium-67

    J Nucl Med

    (1980)
  • DeuelTF et al.

    Platelet factor 4 is chemoattractant for neutrophils and monocytes

  • BaggioliniM et al.

    Neutrophil-activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils

    J Clin Invest

    (1989)
  • ShowellHJ et al.

    The structural relations of synthetic peptides as chemotactic factors and inducers of lysosomal enzyme secretion for neutrophils

    J Exp Med

    (1976)
  • SchiffmannE et al.

    Formylmethionyl peptides as chemoattractants for leukocytes

  • WilliamsLT et al.

    Specific receptor sites for chemotactic peptides on human polymorphonuclear leukocytes

  • SnydermanR et al.

    Leukocyte activation by chemoattractant receptors: Roles of a guanine nucleotide regulatory protein and polyphosphoinositide metabolism

    Rev Infect Dis

    (1987)
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    *

    Supported in part by grants from the R. W. Johnson Pharmaceutical Research Institute and the Shriners, Hospitals for Crippled Children.

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