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A Bivalent Leukotriene B₄ Antagonist for Scintigraphic Imaging of Infectious Foci

¹ Department of Nuclear Medicine, University Medical Centre Nijmegen, Nijmegen, The Netherlands
² Discovery Research, Bristol-Meyers Squibb Medical Imaging, North Billerica, Massachusetts

Several radiolabeled chemotactic peptides have been tested for their suitability to show infection and inflammation. Leukotriene B₄ (LTB₄) receptor-binding ligands could be useful agents for revealing neutrophilic infiltrations because the LTB₄ receptor is abundantly expressed on neutrophils after an inflammatory stimulus. In this study, we investigated the in vivo and in vitro characteristics of a new hydrophilic ¹¹¹In-labeled LTB₄ antagonist. Methods: The LTB₄ antagonist DPC11870-11 was labeled with ¹¹¹In and intravenously injected into New Zealand White rabbits with Escherichia coli infection in the left thigh muscle. The pharmacokinetics and biodistribution were studied by serial scintigraphic imaging (0–24 h after injection) and by ex vivo counting of dissected tissues (6 and 24 h after injection). The receptor-mediated in vivo localization of the compound was investigated in 3 rabbits that received an excess of nonradioactive indium-labeled agent 2 min before the administration of the ¹¹¹In-labeled LTB₄ antagonist. Results: In rabbits with intramuscular E. coli infection, the abscess was visualized as early as 2 h after injection. Accumulation in the abscess increased with time, resulting in excellent images at 6 h after injection. Blood clearance was rapid in the first hours after injection (-half-life = 30 ± 6 min, 85%; ß-half-life = 25.7 ± 0.8 h, 15%). Abscess-to-background ratios, as derived from the region-of-interest analysis, increased to 34 ± 7 at 24 h after injection. The images of both groups showed moderate uptake in the liver, spleen, kidneys, and bone marrow. No activity was seen in the bladder, indicating almost complete retention in the kidneys. The uptake in the abscess could be blocked completely by injection of an excess of nonradioactive agent, indicating a specific receptor-ligand interaction of the radiolabeled agent in the infected tissue. Biodistribution data showed that after saturation of the LTB₄ receptor, the abscess uptake, in percentage injected dose per gram, was significantly reduced (0.03 ± 0.02 vs. 0.24 ± 0.06, P = 0.008). Conclusion: The modified LTB₄ antagonist showed infectious foci rapidly after injection because of specific receptor-ligand interaction. Because of the high abscess-to-background ratios that were obtained and the fact that no accumulation of radioactivity was observed in the gastrointestinal tract, this compound has excellent characteristics for revealing infectious and inflammatory foci.

Key Words: leukotriene B₄ antagonist • infection imaging • scintigraphy

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