Radiolabeled CCK/gastrin peptides for imaging and therapy of CCK2 receptor-expressing tumors

Abstract

Cholecystokinin (CCK) receptors are overexpressed in numerous human cancers, like medullary thyroid carcinomas, small cell lung cancers and stromal ovarian cancers. The specific receptor-binding property of the endogenous ligands for these receptors can be exploited by labeling peptides with a radionuclide and using these as carriers to guide the radioactivity to the tissues that express the receptors. In this way, tumors can be visualized using positron emission tomography and single photon emission computed tomography imaging. A variety of radiolabeled CCK/gastrin-related peptides has been synthesized and characterized for imaging. All peptides have the C-terminal CCK receptor-binding tetrapeptide sequence Trp-Met-Asp-Phe-NH(2) in common or derivatives thereof. This review focuses on the development and application of radiolabeled CCK/gastrin peptides for radionuclide imaging and radionuclide therapy of tumors expressing CCK receptors. We discuss both preclinical studies as well as clinical studies with CCK and gastrin peptides.

Fig. 1

Molecular structure of a CCK8 and b minigastrin: n = 0, MG11; n = 5, MG0

Fig. 2

Serpentine representation of human CCK2R (Foucaud et al. 2008). Amino acids of the binding and/or activation site are marked and numbered (reprinted from Foucaud et al. (2008) with permission of Elsevier)

Fig. 3

Representative animal SPECT/CT image showing biodistribution of ¹¹¹In-DOTA-sCCK8[Phe²(p-CH₂SO₃H), HPG^3,6] at 1 h after administration. Radiotracer uptake is clearly visible in the CCK2R-transfected A431 tumor (left shoulder, arrow) and kidneys, whereas no uptake is noted in the mock-transfected A431 tumor (right flank, arrow head)

Fig. 4

Scintigrams of a patient (anterior and posterior views): first row ^99mTc-Demogastrin 2 at 4 and 24 h, second row ¹¹¹In-DOTA-MG11 at 4 and 24 h and thirrd row ¹¹¹In-DOTA-CCK at 4 and 24 h. Tumor lesions (and stomach) are best visible on ^99mTc-Demogastrin 2 scintigraphy; some lesions are marked with arrows [reprinted with kind permission of Springer Science + Business Media from Fröberg et al. (2009)]