Stereochemistry of Amino Acid Spacers Determines the Pharmacokinetics of (111)In-DOTA-Minigastrin Analogues for Targeting the CCK2/Gastrin Receptor.

Kolenc Peitl, Petra; Tamma, MariaLuisa; Kroselj, Marko; Braun, Friederike; Waser, Beatrice; Reubi, Jean Claude; Sollner Dolenc, Marija; Maecke, Helmut R; Mansi, Rosalba (2015). Stereochemistry of Amino Acid Spacers Determines the Pharmacokinetics of (111)In-DOTA-Minigastrin Analogues for Targeting the CCK2/Gastrin Receptor. Bioconjugate chemistry, 26(6), pp. 1113-1119. American Chemical Society 10.1021/acs.bioconjchem.5b00187

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

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology

UniBE Contributor:

Waser, Beatrice and Reubi-Kattenbusch, Jean-Claude

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1043-1802

Publisher:

American Chemical Society

Language:

English

Submitter:

Doris Haefelin

Date Deposited:

13 Jul 2015 16:12

Last Modified:

17 Oct 2019 11:08

Publisher DOI:

10.1021/acs.bioconjchem.5b00187

PubMed ID:

25971921

BORIS DOI:

10.7892/boris.70210

URI:

https://boris.unibe.ch/id/eprint/70210

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