Highly improved metabolic stability and pharmacokinetics of indium-111-DOTA-gastrin conjugates for targeting of the gastrin receptor

Kolenc-Peitl, Petra; Mansi, Rosalba; Tamma, MariaLuisa; Gmeiner-Stopar, Tanja; Sollner-Dolenc, Marija; Waser, Beatrice; Baum, Richard P; Reubi, Jean-Claude; Maecke, Helmut R (2011). Highly improved metabolic stability and pharmacokinetics of indium-111-DOTA-gastrin conjugates for targeting of the gastrin receptor. Journal of medicinal chemistry, 54(8), pp. 2602-9. Easton, Pa.: American Chemical Society 10.1021/jm101279a

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The development of metabolically stable radiolabeled gastrin analogues with suitable pharmacokinetics is a topic of recent research activity. These imaging vectors are of interest because the gastrin/CCK2 receptor is highly overexpressed in different tumors such as medullary thyroid cancer, neuroendocrine tumors, and SCLC. The drawback of current targeting agents is either their metabolic instability or their high kidney uptake. We present the synthesis and in vitro and in vivo evaluation of 11 (111)In-labeled DOTA-conjugated peptides that differ by their spacer between the peptide and the chelate. We introduced uncharged but hydrophilic spacers such as oligoethyleneglycol, serine, and glutamine. The affinity of all radiopeptides was high with IC(50) values between 0.5 and 4.8 nM. The improvement of human serum stability is 500-fold within this series of compounds. In addition the kidney uptake could be lowered distinctly and the tumor-to-kidney ratio improved almost 60-fold if compared with radiotracers having charged spacers such as glutamic acid.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Service Sector > Institute of Pathology
UniBE Contributor:	Waser, Beatrice, Reubi-Kattenbusch, Jean-Claude
Subjects:	500 Science > 570 Life sciences; biology 600 Technology > 610 Medicine & health
ISSN:	0022-2623
Publisher:	American Chemical Society
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:18
Last Modified:	05 Dec 2022 14:05
Publisher DOI:	10.1021/jm101279a
PubMed ID:	21456601
Web of Science ID:	000289697800003
URI:	https://boris.unibe.ch/id/eprint/5562 (FactScience: 210316)