111In and 68Ga labelled GluDTPA and DOTA-gastrin analogs: A biological and functional analysis

The development of suitable radioligands for targeting CCK-2 receptor expressing tumours, such as medullary thyroid carcinoma, is of clinical interest [1]. In the search for the best CCK-2R binding peptides, we have synthesized and evaluated two gastrin analogs. DGlu(1)-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 (DGlu(1)-minigastrin) and DGlu-Glu(5)-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 (DGlu-Glu(5)-minigastrin) have been synthesized on solid phase utilizing the Fmoc strategy. The N-terminal portion of both conjugates was derivatized by introducing the DTPAGlu or DOTA chelators to allow radiolobeling with 111In(III) and 68Ga(III) respectively. Saturation binding experiments were performed on A431-CCK2R overexpressing cells. All compounds showed Kd values in the nM range. Biodistribution experiments showed higher specific uptake of 111In-GluDTPA-DGlu-Glu(5)-minigastrin on CCK2-R overexpressing xenografts compared to 111In-GluDTPA-DGlu(1)-minigastrin and to previously described 111In-GluDTPA-CCK8. The higher retention levels were associated with markedly elevated and undesired kidney uptake for 111In-GluDTPA-DGlu-Glu(5)-minigastrin compared to the other compounds. Similarly, 68Ga-DOTA-DGlu(1)-minigastrin showed slightly lower specific uptake in receptor positive xenografts (see table) but much lower kidney retention compared to 68Ga-DOTA-DGlu(5)-minigastrin. Current indications suggest that the 5 Glu N-terminal residues while improving receptor targeting cause unacceptably high kidney retention. Future work will focus on improving the receptor targeting of the shorter DGlu(1)-minigastrin or CCK8 peptide sequences.