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Inflammation and Infection Imaging with a ^99mTc-Neutrophil Elastase Inhibitor in Monkeys

Divisions of Nuclear Medicine and Pathology, University of Massachusetts Medical School, Worcester, Massachusetts
Dyax Corporation, Cambridge, Massachusetts

Correspondence: For correspondence or reprints contact: Donald J. Hnatowich, PhD, Division of Nuclear Medicine, University of Massachusetts Medical Center, Worcester, MA 01655.

ABSTRACT

A radiolabeled human neutrophil elastase inhibitor (EPI-HNE-2) may represent an improved nuclear medicine imaging agent for inflammation and infection. This peptide displays rapid pharmaco-kinetics due to its low molecular weight and localizes specifically on neutrophil elastase released in inflammatory sites by activated neutrophils. Methods: In this investigation, the peptide was radiolabeled with ^99mTc using N-hydroxysuccinimidyl S-acetylmercaptoacetyltriglycline (NHS-MAG₃) as a bifunctional chelator and was administered on 18 occasions to 5 rhesus monkeys with inflammation/infection. Results: Plasma clearance was rapid, with liver and kidneys representing the major organs of accumulation. No evidence of toxicity, dosage effects, or circulating antiMAG₃-EPI-HNE-2 antibodies was observed. Specificity of localization was established using radiolabeled bovine pancreatic trypsin inhibitor (a non-hNE-binding peptide of similar size) as a nonspecific negative control peptide and by predosing with unlabeled EPI-HNE-2 to block receptor sites before the administration of radiolabeled EPI-HNE-2. The ability of radiolabeled EPI-HNE-2 to image inflammation/infection was evaluated in 12 studies in monkeys receiving only radiolabeled EPI-HNE-2 and with lesions in the arm, shoulder, or lower back. Positive images were obtained in all studies, uptake was apparent almost immediately, and images were still positive 24 h later. As a positive control, animals also received nonspecific IgG antibody radiolabeled with ^99mTc either directly or by NHS-MAG₃. Compared with labeled antibody, plasma clearance of ^99mTc was faster with labeled EPI-HNE-2 and accumulation in liver and heart was lower. Uptake of radioactivity in the inflammation was higher during the first hour with EPI-HNE-2 versus antibody but lower thereafter. Conclusion: When radiolabeled with ^99mTc, EPI-HNE-2 localized specifically in inflammations in a monkey model and provided early images of diagnostic quality.

Key Words: ^99mTc-peptide • inflammation and infection imaging

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