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Steps toward High Specific Activity Labeling of Biomolecules for Therapeutic Application:  Preparation of Precursor [188Re(H2O)3(CO)3]+ and Synthesis of Tailor-Made Bifunctional Ligand Systems

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posted on 11.05.2002, 00:00 by Roger Schibli, Rolf Schwarzbach, Roger Alberto, Kirstin Ortner, Helmut Schmalle, Cécile Dumas, André Egli, P. August Schubiger
Two kit preparations of the organometallic precursor [188Re(H2O)3(CO)3]+ in aqueous media are presented. Method A uses gaseous carbon monoxide and amine borane (BH3·NH3) as the reducing agent. In method B CO(g) is replaced by K2[H3BCO2] that releases carbon monoxide during hydrolysis. Both procedures afford the desired precursor in yields >85% after 10 min at 60 °C. HPLC and TLC analyses revealed 7 ± 3% of unreacted 188ReO4- and <5% of colloidal 188ReO2. Solutions of up to 14 GBq/mL Re-188 have been successfully carbonylated with these two methods. The syntheses of two tailor-made bifunctional ligand systems for the precursor [188Re(H2O)3(CO)3]+ are presented. The tridentate chelates consist of a bis[imidazol-2-yl]methylamine or an iminodiacetic acid moiety, respectively. Both types of ligand systems have been prepared with alkyl spacers of different length and a pendent primary amino or carboxylic acid functionality, enabling the amidic linkage to biomolecules. The tridentate coordination of the ligands to the rhenium-tricarbonyl core could be elucidated on the macroscopic level by X-ray structure analyses and 1D and 2D NMR experiments of two representative model complexes. On the nca level, the ligands allow labeling yields >95% with [188Re(H2O)3(CO)3]+ under mild reaction conditions (PBS buffer, 60 °C, 60 min) at ligand concentrations between 5 × 10-4 M and 5 × 10-5 M. Thus, specific activities of 22−220 GBq per μmol of ligand could be achieved. Incubation of the corresponding Re-188 complexes in human serum at 37 °C revealed stabilities between 80 ± 4% and 45 ± 10% at 24 h, respectively, and 63 ± 3% and 34 ± 3% at 48 h postincubation in human serum depending on the chelating system. Decomposition product was mainly 188ReO4-. The routine kit-preparation of the precursor [188Re(H2O)3(CO)3]+ in combination with tailor-made ligand systems enables the organometallic labeling of biomolecules with unprecedented high specific activities.

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