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^99mTc-HYNIC-[Tyr³]-Octreotide for Imaging Somatostatin-Receptor-Positive Tumors: Preclinical Evaluation and Comparison with ¹¹¹In-Octreotide

Nuclear Medicine Research Laboratory, St. Bartholomew's Hospital, West Smithfield, London, United Kingdom

Correspondence: For correspondence or reprints contact: Stephen J. Mather, PhD, Nuclear Medicine Research Laboratory, St. Bartholomew's Hospital, West Smithfield, London EC1 7BE, UK.

ABSTRACT

In this paper we describe the preclinical evaluation of ^99mTc-hydrazinonicotinyl-Tyr³-octreotide (HYNIC-TOC) using different coligands for radiolabeling and a comparison of their in vitro and in vivo properties with ¹¹¹In-diethylenetriaminepentaacetic acid (DTPA)-octreotide. Methods: HYNIC-TOC was radiolabeled at high specific activities using tricine, ethylenediaminediacetic acid (EDDA), and tricine-nicotinic acid as coligand systems. Receptor binding was tested using AR42J rat pancreatic tumor cell membranes. Intemalization and protein binding studies were performed, and biodistribution and tumor uptake were determined in AR42J tumor-bearing nude mice. Results: All ^99mTc-labeled HYNIC peptides showed retained somatostatin-receptor binding affinities (K_d, < 2.65 nM). Protein binding and intemalization rates were dependent on the coligand used. Specific tumor uptake between 5.8 and 9.6 percentage injected dose per gram (%ID/g) was found for the ^99mTc-labeled peptides, compared with 4.3 %ID/g for ¹¹¹In-DTPA-octreotide. Tricine as coligand showed higher activity levels in muscle, blood, and liver, whereas tricine-nicotinic acid produced significant levels of activity in the gastrointestinal tract. EDDA showed the most promising overall biodistribution profile, with tumor-to-liver and tumor-to-gastrointestinal tract ratios similar to those obtained with ¹¹¹In-DTPA-octreotide, lower ratios in blood and muscle, but considerably higher tumor-to-kidney ratios. Conclusion: TOC can be radiolabeled to high specific activities using HYNIC as a bifunctional chelator. The high specific tumor uptake, rapid blood clearance, and predominantly renal excretion make ^99mTc-EDDA-HYNIC-TOC a promising candidate for an alternative to ¹¹¹In-DTPA-octreotide for tumor imaging.

Key Words: somatostatin • octreotide • hydrazinonicotinamide • _99mTc

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