Evaluation of three different families of bombesin receptor radioantagonists for targeted imaging and therapy of gastrin releasing peptide receptor (GRP-R) positive tumors.

Mansi, Rosalba; Abiraj, Keelara; Wang, Xuejuan; Tamma, Maria Luisa; Gourni, Eleni; Cescato, Renzo; Berndt, Sandra; Reubi, Jean-Claude; Maecke, Helmut R (2015). Evaluation of three different families of bombesin receptor radioantagonists for targeted imaging and therapy of gastrin releasing peptide receptor (GRP-R) positive tumors. Journal of medicinal chemistry, 58(2), pp. 682-691. American Chemical Society 10.1021/jm5012066

[img] Text
jm5012066.pdf - Published Version
Restricted to registered users only
Available under License Publisher holds Copyright.

Download (2MB) | Request a copy

Two new classes of radiolabeled GRP receptor antagonists are studied and compared with the well-established statine-based receptor antagonist DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (RM2, 1; DOTA:1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; Sta:(3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid). The bombesin-based pseudopeptide DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Leuψ(CHOH-CH2)-(CH2)2-CH3 (RM7, 2), and the methyl ester DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-OCH3 (ARBA05, 3) analogues are labeled with (111)In and evaluated in vitro in PC-3 cell line and in vivo in PC-3 tumor-bearing nude mice. Antagonist potency was assessed by immunofluorescence-based receptor internalization and Ca(2+) mobilization assays. The conjugates showed good binding affinity, the IC50 value of 2 (3.2 ± 1.8 nM) being 2 and 10 times lower than 1 and 3. Compared to (111)In-1, (111)In-2 showed higher uptake in target tissues such as pancreas (1.5 ± 0.5%IA/g and 39.8 ± 9.3%IA/g at 4 h, respectively), whereas the compounds had similar tumor uptake (11.5 ± 2.4%IA/g and 11.8 ± 3.9%IA/g at 4h, respectively). The displacement of the radioligand in vivo was different in different receptor positive organs and depended on the displacing peptide.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Pavillon 52 > Forschungsgruppe Klinische Radiopharmazie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Pavillon 52 > Forschungsgruppe Klinische Radiopharmazie

UniBE Contributor:

Cescato, Renzo and Reubi, Jean-Claude

Subjects:

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

ISSN:

0022-2623

Publisher:

American Chemical Society

Language:

English

Submitter:

Doris Haefelin

Date Deposited:

13 Jul 2015 10:22

Last Modified:

13 Jul 2015 10:22

Publisher DOI:

10.1021/jm5012066

PubMed ID:

25474596

BORIS DOI:

10.7892/boris.70214

URI:

https://boris.unibe.ch/id/eprint/70214

Actions (login required)

Edit item Edit item
Provide Feedback