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Preclinical and Initial Clinical Evaluation of ¹¹¹In-Labeled Nonsulfated CCK₈ Analog: A Peptide for CCK-B Receptor-Targeted Scintigraphy and Radionuclide Therapy

Department of Nuclear Medicine, University Hospital Dijkzigt, Rotterdam, The Netherlands
Department of Pathology, University of Berne, Berne, Switzerland
Mallinckrodt, Inc., St. Louis, Missouri

Correspondence: For correspondence or reprints contact: Marion de Jong, PhD, Departmeny of Nuclear Medicine, V220, University Hospital Rotterdam, 3015 GD Rotterdam, The Netherlands.

ABSTRACT

The presence of cholecystokinin (CCK)-B (gastrin) receptors has been shown in more than 90% of medullary thyroid cancers (MTCs) and in a high percentage of small cell lung cancers, stromal ovarium cancers and several other tumor types. Methods: The aim of this study was to evaluate in vitro and in vivo whether ¹¹¹In-labeled CCK-B receptor-specific CCK₈ analog [D-Asp²⁶-Nle^28,31]CCK_26–33 (D-Asp-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH₂) is suitable for CCK-B receptor scintigraphy based on the finding that unlabeled nonsulfated diethylenetriamine pentaacidic acid [DTPA⁰]CCK₈ and tetraazacyclododecanetetraacetic acid [DOTA⁰]CCK₈ analogs show high and specific binding for CCK-B receptors in human tumors. Fifty percent inhibitory concentrations were in the low nanomolar range. Results: In vitro, [¹¹¹In-DOTA⁰]CCK₈ showed specific internalization in CCK-B receptor-positive rat pancreatic tumor cells AR42J. Internalization of the analog appeared to be time and temperature dependent and receptor specific. From the data obtained with [¹¹¹In-DOTA⁰]CCK₈ and ¹²⁵I-gastrin, the latter being a specific ligand for the CCK-B receptor, the rat pancreatic cell line CA20948 also appeared to be CCK-B receptor positive. This provides an in vitro and in vivo rat tumor model because this cell line can be grown to solid tumors in Lewis rats. In vivo biodistribution experiments in CA20948 tumor-bearing Lewis rats showed rapid clearance of [¹¹¹In-DOTA⁰]CCK₈, and specific uptake was found in the CCK-B receptor-expressing stomach and tumor. Furthermore, comparing [¹¹¹In-DOTA⁰]CCK₈ with the radioiodinated nonsulfated CCK₁₀ analog (D-Tyr-Gly-Asp-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH₂), both ligands having high affinity for the CCK-B receptor, tumor-to-blood ratios were significantly higher for [¹¹¹In-DOTA⁰]CCK₈ than for ¹²⁵I-CCK₁₀, analogous to the findings with radioiodinated and ¹¹¹In-labeled octreotide. The study in humans with [¹¹¹In-DTPA⁰]CCK₈ showed receptor-specific uptake in the CCK-B receptor-positive stomach and in metastases in the neck region up to 48 h after injection. Conclusion: [¹¹¹In-DOTA⁰]CCK₈ is most promising for scintigraphy and, after coupling to therapeutic radionuclides, for radionuclide therapy of human CCK-B receptor-positive tumors such as MTC and small cell lung cancer.

Key Words: cholecystokenin receptors • [DOTA⁰]CCK₈ • [DTPA⁰]CCK₈ • ¹¹¹In • tumor scintigraphy • radionuclide therapy • medullary thyroid cancers

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