99mTc-Labeling and in Vivo Studies of a Bombesin Analogue with a Novel Water-Soluble Dithiadiphosphine-Based Bifunctional Chelating Agent

Bioconjugate Chem., 10 (2), 254 -260, 1999. 10.1021/bc980096a S1043-1802(98)00096-2
Web Release Date: February 9, 1999

^99mTc-Labeling and in Vivo Studies of a Bombesin Analogue with a Novel Water-Soluble Dithiadiphosphine-Based Bifunctional Chelating Agent

Srinivasa R. Karra, Roger Schibli, Hariprasad Gali, Kattesh V. Katti, Timothy J. Hoffman, Chris Higginbotham, Gary L. Sieckman, and Wynn A. Volkert*

Department of Radiology, Department of Chemistry, and Department of Medicine, University of Missouri-Columbia, Columbia, Missouri 65211, and H. S. Truman Memorial Veterans Hospital, Columbia, Missouri 65212

Received August 19, 1998

Revised December 2, 1998

Abstract:

Recent progress in the synthesis of water-soluble phosphine ligand systems and their corresponding ^99mTc complexes prompted the development of a new bifunctional chelating agent (BFCA) based on a tetradentate dithiadiphosphine framework (P₂S₂-COOH). The detailed synthesis of this new BFCA is described here. The corresponding ^99mTc complex, ^99mTc-P₂S₂-COOH, can be formed in >95% yield. To demonstrate the potential of this chelate to efficiently label peptides, ^99mTc-P₂S₂-COOH was coupled to the N-terminal region of the truncated nine-amino acid bombesin analogue, 5-Ava-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH₂ [BBN⁽⁷^-¹⁴⁾], to form ^99mTc-P₂S₂-BBN⁽⁷^-¹⁴⁾. Conjugation to the peptide was performed in borate buffer (pH 8.5) by applying the prelabeling approach in yields of >60%. In competitive binding assays, using Swiss 3T3 mouse fibroblast cells against [¹²⁵I-Tyr⁴]bombesin, Re-P₂S₂-BBN⁽⁷^-¹⁴⁾ exhibited an IC₅₀ value of 0.8 ± 0.4 nM. The pharmacokinetic studies of ^99mTc-P₂S₂-BBN⁽⁷^-¹⁴⁾ and its ability to target tissue expressing gastrin-releasing peptide (GRP) receptors were performed in normal mice. The ^99mTc-P₂S₂-BBN⁽⁷^-¹⁴⁾ exhibited fast and efficient clearance from the blood pool (0.6 ± 0.1% ID, 4 h postinjection) and excretion through the renal and hepatobiliary pathways (56.4 ± 8.2 and 28.1 ± 7.9% ID, 4 h postinjection, respectively). Significant uptake in the pancreas was observed (pancreatic acini cells express bombesin/GRP receptors), producing pancreas:blood and pancreas:muscle ratios of ca. 22 and 80, respectively, at 4 h postinjection.

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