Development of a potent DOTA-conjugated bombesin antagonist for targeting GRPr-positive tumours

Autor: Flavio Forrer, Rosalba Mansi, Renzo Cescato, Xuejuan Wang, Keith Graham, Helmut R. Maecke, Beatrice Waser, Sandra Borkowski, Jean Claude Reubi
Rok vydání: 2010
Předmět:
Zdroj: Mansi, Rosalba; Wang, Xuejuan; Forrer, Flavio; Waser, Beatrice; Cescato, Renzo; Graham, Keith; Borkowski, Sandra; Reubi, Jean-Claude; Maecke, Helmut R (2011). Development of a potent DOTA-conjugated bombesin antagonist for targeting GRPr-positive tumours. European journal of nuclear medicine and molecular imaging, 38(1), pp. 97-107. Berlin: Springer 10.1007/s00259-010-1596-9
ISSN: 1619-7089
1619-7070
DOI: 10.1007/s00259-010-1596-9
Popis: Radiolabelled somatostatin-based antagonists show a higher uptake in tumour-bearing mouse models than agonists of similar or even distinctly higher receptor affinity. Very similar results were obtained with another family of G protein-coupled receptor ligands, the bombesin family. We describe a new conjugate, RM2, with the chelator DOTA coupled to D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH(2) via the cationic spacer 4-amino-1-carboxymethyl-piperidine for labelling with radiometals such as (111)In and (68)Ga.RM2 was synthesized on a solid support and evaluated in vitro in PC-3 cells. IC(50) and K(d) values were determined. The antagonist potency was evaluated by immunofluorescence-based internalization and Ca(2+) mobilization assays. Biodistribution studies were performed in PC-3 and LNCaP tumour-bearing mice with (111)In-RM2 and (68)Ga-RM2, respectively. PET/CT studies were performed on PC-3 and LNCaP tumour-bearing nude mice with (68)Ga-RM2.RM2 and (111)In-RM2 are high-affinity and selective ligands for the GRP receptor (7.7 ± 3.3 nmol/l for RM2; 9.3 ± 3.3 nmol/l for (nat)In-RM2). The potent antagonistic properties were confirmed by an immunofluorescence-based internalization and Ca(2+) mobilization assays. (68)Ga- and (111)In-RM2 showed high and specific uptake in both the tumour and the pancreas. Uptake in the tumour remained high (15.2 ± 4.8%IA/g at 1 h; 11.7 ± 2.4%IA/g at 4 h), whereas a relatively fast washout from the pancreas and the other abdominal organs was observed. Uptake in the pancreas decreased rapidly from 22.6 ± 4.7%IA/g at 1 h to 1.5 ± 0.5%IA/g at 4 h.RM2 was shown to be a potent GRPr antagonist. Pharmacokinetics and imaging studies indicate that (111)In-RM2 and (68)Ga-RM2 are ideal candidates for clinical SPECT and PET studies.
Databáze: OpenAIRE
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