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Radiolabeled Peptides for Targeting Cholecystokinin-B/Gastrin Receptor-Expressing Tumors

Department of Nuclear Medicine, Georg-August-University, Göttingen, Germany
Department of Endocrinology, Ruprecht-Karl-University, Heidelberg, Germany

Correspondence: For correspondence or reprints contact: Thomas M. Behr, MD, Department of Nuclear Medicine, Georg-August-University, Robert-Koch-Str. 40, D-37075 Göttingen, Germany.

ABSTRACT

The high sensitivity of pentagastrin stimulation in detecting primary or metastatic medullary thyroid cancer (MTC) suggests widespread expression of the corresponding receptor type on human MTC. Indeed, autoradiographic studies have demonstrated cholecystokinin (CCK)-B/gastrin receptors not only in more than 90% of MTCs but also in a high percentage of small cell lung cancers, some ovarian cancers, astrocytomas and potentially a variety of adenocarcinomas. The aim of this study was to systematically screen and optimize, in a preclinical model and a pilot clinical study, suitable radioligands for targeting CCK-B receptors in vivo. Methods: A variety of CCK/gastrin-related peptides, all bearing the C-terminal CCK receptor-binding tetrapeptide sequence Trp-Met-Asp-PheNH₂ or derivatives thereof, were studied. They were radioiodinated by the lodogen or Bolton-Hunter procedures. The peptides were members of the gastrin or CCK families, which differ by the intramolecular position of a tyrosyl moiety. Their stability and affinity were studied in vitro and in vivo; their biodistribution and therapeutic efficacy were tested in nude mice bearing subcutaneous human MTC xenografts. Diethylenetriamine pentaacetic acid (DTPA) derivatives of suitable peptides were synthesized successfully, and their preclinical and initial clinical evaluations were performed, labeled with ¹¹¹In. Results: All members of the CCK or gastrin families were stable in serum (with half-lives of several hours at 37°C); nevertheless, the stability of those peptides bearing N-terminal pGlu residues or D-amino acids was significantly higher. In accordance with their comparably low affinity, nonsulfated members of the CCK family showed fairly low uptake in the tumor and other CCK-B receptor-expressing tissues. Sulfated CCK derivatives performed significantly better but also displayed a comparably high uptake in normal CCK-A receptor expressing tissues. This effect was probably due to their similar affinity for both CCK-A and CCK-B receptors. Best tumor uptake and tumor-to-nontumor ratios were obtained with members of the gastrin family because of their selectivity and affinity for the CCK-B receptor subtype. Pilot therapy experiments in MTC bearing animals showed significant antitumor efficacy compared with untreated controls. DTPA derivatives of minigastrin were successfully developed. In a pilot clinical study, radioiodinated and ¹¹¹In-labeled derivatives showed excellent targeting of physiological CCK-B receptor-expressing organs, as well as all known tumorsites. Conclusion: CCK/gastrin analogs maybe a useful new class of receptor-binding peptides for diagnosis and therapy of CCK-B receptor-expressing tumors, such as MTC or small cell lung cancer. Nonsulfated gastrin derivatives maybe preferable because of their CCK-B receptor selectivity, hence lower accretion in normal CCK-A receptor-expressing organs.

Key Words: gastrin • cholecystokinin • cholecystokinin-B/gastrin receptors • radiolabeled peptides • medullary thyroid cancer • small cell lung cancer

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