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

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 chemoattractant 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/mumole). 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.