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Imaging Pulmonary Emboli and Deep Venous Thrombi with ^99mTc-Bitistatin, a Platelet-Binding Polypeptide from Viper Venom

Nuclear Medicine Division, Department of Diagnostic Imaging, Sol Sherry Thrombosis Research Center, and Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania
Division of Radiation Health Sciences, Johns Hopkins Medical Institute, Baltimore, Maryland

Correspondence: For correspondence or reprints contact: Linda C. Knight, PhD, Nuclear Medicine Division, Temple University Hospital, 3401 N. Broad St., Philadelphia, PA 19140.

ABSTRACT

An imaging test that could locate both pulmonary emboli (PE) and their source, active deep venous thrombi (DVT), would be valuable in patient management. Bitistatin, an 83-amino-acid polypeptide isolated from Bitis arietans venom, binds avidly to the glycoprotein IIb/IIIa receptor on platelets. The goal of this study was to label bitistatin with ^99mTc and assess its potential for imaging thrombi and emboli in vivo. Methods: Molecular modeling of bitistatin indicated that its primary amines are located on the opposite side of the molecule from the receptor-binding domain. The primary amines were reacted with succinimidyl-4-hydrazino nicotinate hydrochloride to place 2.4 hydrazino nicotinate (Hn) chelating groups per peptide molecule. Hn-bitistatin was labeled by incubation with ^99mTc-glucoheptonate to 96 TBq/mmol and then tested for binding to platelets in vitro and for imaging of 24-h-old DVT and PE in a canine model used previously for other thrombus tracers. Results: ^99mTc-Hn-bitistatin bound to stimulated platelets with a dissociation constant (K_d) = 32 nmoI/L, similar to that of ¹²⁵I-bitistatin (K_d = 41 nmoI/L). In vivo, focal uptake was observed in planar images as early as 30 min (DVT) and 60 min (PE) after injection. Lesion uptake of ^99mTc-Hn-bitistatin at 4 h after injection was calculated in terms of percentage injected dose per gram (%ID/g) of tissue and averaged 0.89 %ID/g PE and 0.79 %ID/g DVT. Lesion-to-background ratios averaged 34:1 (PE-to-lung), 18:1 (DVT-to-blood), and 284:1 (DVT-to-muscle). These values were not significantly different from iodinated bitistatin, but uptakes were higher than other tracers tested in the same model. Conclusion: ^99mTc-Hn-bitistatin retains the functional activity of the iodinated peptide, has higher DVT and PE uptakes than other thrombus tracers in this standardized model, and has target-to-background characteristics suitable for imaging both PE and DVT in a single test.

Key Words: ^99mTc-bitistatin • deep venous thrombosis • pulmonary embolism • direct visualization with ^99mTc-bitistatin • thrombosis imaging with ^99mTc-bitistatin