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.

111In and 68Ga labelled GluDTPA and DOTA-gastrin analogs: A biological and functional analysis / Tesauro, Diego; Tornesello, A. L.; Accardo, Antonella; A., Morisco; C., Arra; A., Barbieri; M., Aurilio; L., Aloj; Morelli, Giancarlo. - STAMPA. - (2010), pp. 1-1. (Intervento presentato al convegno 12th Naples Workshop on bioactive peptides tenutosi a Napoli nel 4-6 giugno 2010).

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

TESAURO, DIEGO;ACCARDO, ANTONELLA;MORELLI, GIANCARLO
2010

Abstract

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.
2010
111In and 68Ga labelled GluDTPA and DOTA-gastrin analogs: A biological and functional analysis / Tesauro, Diego; Tornesello, A. L.; Accardo, Antonella; A., Morisco; C., Arra; A., Barbieri; M., Aurilio; L., Aloj; Morelli, Giancarlo. - STAMPA. - (2010), pp. 1-1. (Intervento presentato al convegno 12th Naples Workshop on bioactive peptides tenutosi a Napoli nel 4-6 giugno 2010).
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/374954
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