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Stereochemistry of amino acid spacers determines the pharmacokinetics of 111In-DOTA-minigastrin analogues for targeting of the CCK2/gastrin receptor
Kolenc, Petra, 1976- ...
Metabolic instability and high kidney retention of minigastrin (MG) analogues hampers their suitability for peptide receptor radionuclide therapy of CCK2/gastrin receptor expressing tumors. High ...kidney retention has been related to the N-terminal glutamic acids and could be substantially reduced byco-injection of polyglutamic acids or gelofusine. The aim of the present study was to investigate the influence of stereochemistry of N-terminal amino acid spacer on enzymatic stability and pharmacokinetics of 111In-DOTA-(D-Glu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 (111In-PP11-D) and 111In-DOTA-(L-Glu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 (111In-PP11-L). By use of circular dichroism measurements we demonstrate the important role of the secondary structure on the pharmacokinetics of the two MG analogues. The higher in vitro serum stability together with better tumor-to-kidney ratio of the (D-Glu)6-congener indicates that this MG analogue might be a good candidate for further clinical study.
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