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Technetium-99m-Labeled Hydrazino Nicotinamide Derivatized Chemotactic Peptide Analogs for Imaging Focal Sites of Bacterial Infection

Nuclear Medicine Division of the Department of Radiology, the Clinical Investigation and Arthritis Units of the Medical Service and the Surgical Service, Massachusetts General Hospital
Shriners Burns Institute, Boston, Massachusetts
R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey
Johnson Matthey Pharmaceutical Research, West Chester, Pennsylvania

Correspondence: For correspondence or reprints contact: Alan J. Fischman, MD, PhD, Div. of Nuclear Medicine, Massachusetts General Hospital, Fruit St., Boston, MA 02114.

ABSTRACT

We synthesized and evaluated four hydrazino nicotinamide (HYNIC) derivatized chemotactic peptide analogs: For-NIeLFK-HYNIC (HP1), For-MLFK-HYNIC (HP2), For-MLFNH(CH2)6NH-HYNIC (HP3), and For-MLF-(D)-K-HYNIC (HP4), for in vitro bioactivity and receptor binding. The peptides were radiolabeled with ^99mTc via a glucoheptonate co-ligand and their biodistribution determined in rats (n = 6/time point) at 5, 30, 60 and 120 min after injection. Localization of the peptides at sites of deep thigh Escherichia coli infection was determined by radioactivity measurements on excised tissues in rats (n = 6/time point) and rabbits as well as scintillation camera imaging in rabbits (n = 6). All peptides maintained biological activity (EC₅₀s for O₂ production by human PMNs: 12–500 nM) and the ability to bind to the oligopeptide chemoattractant receptor on human PMNS (EC₅₀s for binding: 0.12–40 nM). After incubation with ^99mTc-glucoheptonate, radiolabeled peptides were isolated by HPLC at specific activities of > 10,000 mCi/µM. Technetium-99m-labeled peptides retained receptor binding with EC₅₀s < 10 nM. Blood clearance of all four peptides was rapid. Biodistributions of the individual peptides were similar, with low levels of accumulation in most normal tissues. In rats, all of the peptides concentrated at the infection sites (T/B ratio: 2.5–3:1) within 1 hr of injection. In rabbits, outstanding images of the infection sites were obtained, with T/B ratios of >20:1 at 15 hr after injection. This study demonstrates that ^99mTc-labeled chemotactic peptide analogs are effective agents for the external imaging of focal sites of infection.

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