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Tetraamine-derived bifunctional chelators for technetium-99m labelling : synthesis, bioconjugation and evaluation as targeted SPECT imaging probes for GRP-receptor-positive tumours

Abiraj, Keelara and Mansi, Rosalba and Tamma, Maria-Luisa and Forrer, Flavio and Cescato, Renzo and Reubi, Jean Claude and Akyel, Kayhan G. and Maecke, Helmut R.. (2010) Tetraamine-derived bifunctional chelators for technetium-99m labelling : synthesis, bioconjugation and evaluation as targeted SPECT imaging probes for GRP-receptor-positive tumours. Chemistry, a European journal, Vol. 16, H. 7. pp. 2115-2124.

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Official URL: http://edoc.unibas.ch/dok/A6003431

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Abstract

Owing to its optimal nuclear properties, ready availability, low cost and favourable dosimetry, (99m)Tc continues to be the ideal radioisotope for medical-imaging applications. Bifunctional chelators based on a tetraamine framework exhibit facile complexation with Tc(V)O(2) to form monocationic species with high in vivo stability and significant hydrophilicity, which leads to favourable pharmacokinetics. The synthesis of a series of 1,4,8,11-tetraazaundecane derivatives (01-06) containing different functional groups at the 6-position for the conjugation of biomolecules and subsequent labelling with (99m)Tc is described herein. The chelator 01 was used as a starting material for the facile synthesis of chelators functionalised with OH (02), N(3) (04) and O-succinyl ester (05) groups. A straightforward and easy synthesis of carboxyl-functionalised tetraamine-based chelator 06 was achieved by using inexpensive and commercially available starting materials. Conjugation of 06 to a potent bombesin-antagonist peptide and subsequent labelling with (99m)Tc afforded the radiotracer (99m)Tc-N4-BB-ANT, with radiolabelling yields of <97% at a specific activity of 37 GBq micromol(-1). An IC(50) value of (3.7+/-1.3) nM was obtained, which confirmed the high affinity of the conjugate to the gastrin-releasing-peptide receptor (GRPr). Immunofluorescence and calcium mobilisation assays confirmed the strong antagonist properties of the conjugate. In vivo pharmacokinetic studies of (99m)Tc-N4-BB-ANT showed high and specific uptake in PC3 xenografts and in other GRPr-positive organs. The tumour uptake was (22.5+/-2.6)% injected activity per gram (% IA g(-1)) at 1 h post injection (p.i.). and increased to (29.9+/-4.0)% IA g(-1) at 4 h p.i. The SPECT/computed tomography (CT) images showed high tumour uptake, clear background and negligible radioactivity in the abdomen. The promising preclinical results of (99m)Tc-N4-BB-ANT warrant its potential candidature for clinical translatio
Faculties and Departments:03 Faculty of Medicine > Bereich Querschnittsfächer (Klinik) > Radiologie USB > Nuklearmedizin (Wild)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Querschnittsfächer (Klinik) > Radiologie USB > Nuklearmedizin (Wild)
UniBasel Contributors:Forrer, Flavio
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Wiley-VCH Verlag
ISSN:0947-6539
Note:Publication type according to Uni Basel Research Database: Journal article
Last Modified:07 Dec 2012 13:04
Deposited On:07 Dec 2012 13:03

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