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Preclinical Evaluation of a New, Stabilized Neurotensin(8–13) Pseudopeptide Radiolabeled with ^99mTc

¹ Center for Radiopharmaceutical Science, Paul Scherrer Institute, Villigen, Switzerland
² Department of Organic Chemistry, Vrije Universiteit Brussel, Brussels, Belgium

The rapid degradation of neurotensin (NT) limits its clinical use in cancer imaging and therapy. Thus, a new NT(8–13) pseudopeptide, NT-VIII, was synthesized. Some changes were introduced in the sequence of NT(8–13) to stabilize the molecule against enzymatic degradation: Arg⁸ was N-methylated, and Lys and Tle replaced Arg⁹ and Ile¹², respectively. Finally, (NHis)Ac was coupled to the N-terminus for ^99mTc(CO)₃ labeling. This peptide was characterized both in vitro and in vivo. Methods: The new analog was labeled with ^99mTc(CO)₃. Its metabolic stability was analyzed both in human plasma and in HT-29 cells. Binding properties, receptor downregulation, and internalization were tested with HT-29 cells. Biodistribution was evaluated in nude mice with HT-29 xenografts. Results: ^99mTc(CO)₃NT-VIII showed a high stability in plasma, where most of the peptide remained intact after 24 h of incubation at 37°C. However, the degradation in HT-29 cells was more rapid (46% of intact ^99mTc(CO)₃NT-VIII after 24 h at 37°C). Binding to NT1 receptors (NTR1) was saturable and specific. Scatchard analysis showed a high affinity for ^99mTc(CO)₃NT-VIII, with a dissociation constant similar to ¹²⁵I-NT (1.8 vs. 1.6 nmol/L). After interacting with NTR1, ^99mTc(CO)₃NT-VIII was rapidly internalized, with more than 90% internalized after 30 min. It also distributed and cleared rapidly in nude mice bearing HT-29 xenografts. The highest rates of accumulation were found in kidney and tumor at all time points tested. Tumor uptake was highly specific because it could be blocked by coinjection with a high dose of (NHis)Ac-NT(8–13). Tumors were clearly visualized in scintigraphy images. Conclusion: The changes that were introduced stabilized the molecule against enzymatic degradation without affecting binding properties. Moreover, the increase in stability enhanced tumor uptake, making this derivative a promising candidate for clinical use.

Key Words: neurotensin(8–13) • internalization • biodistribution • scintigraphy • metabolic stability

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