Gastrin and cholecystokinin peptide-based radiopharmaceuticals: an in vivo and in vitro comparison

The development of suitable radioligands for targeting CCK-2 receptor expressing tumors, such as medullary thyroid carcinoma, is of great clinical interest. In the search for the best CCK-2R binding peptides, we have synthesized, evaluated and compared the CCK8 peptide (Asp-Tyr-Met-Gly-Trp-Met-Asp-Phe-NH2) and two gastrin analogs commonly referred to as MG0 (DGlu-Glu(5)-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2) and MG11 (DGlu(1)-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2). The N-terminal portion of the three peptide sequences was derivatized by introducing the DTPAGlu or DOTA chelators to allow radiolobeling with In-111(III) and Ga-68(III), respectively. Saturation binding and cellular internalization experiments were performed on A431 cells overexpressing CCK2R (A431-CCK2R). All compounds showed Kd values in the nM range and were internalized with similar rates in CCK2 receptor overexpressing cells. Biodistribution experiments showed higher specific uptake of both MG0-based compounds compared to conjugates containing the CCK8 and MG11 peptide sequences. The higher retention levels of MG0-based peptides were associated with markedly elevated and undesired kidney uptake compared to the other compounds. Current indications suggest that the 5 Glu N-terminal residues while improving peptide stability and receptor-mediated tumor uptake cause unacceptably high kidney retention. Although displaying lower absolute tumor uptake values, the DOTA-coupled CCK8 peptide provided the best tumor to kidney uptake ratio and appears more suitable as lead compound for improvement of radiopharmaceutical properties. Copyright (C) 2011 European Peptide Society and John Wiley & Sons, Ltd.