Very stable 188Re-S4 chelates for labelling biomolecules. Preparation with highly concentrated perrhenate eluates

Aim: The preparation and stability of a new 188Re-S4-complex [S4 (1-aza-18-crown-6)(O)C-C(SH)-C(SH)-C(O)NH-(CH2)3-NH-(CH2)3-NHC(O)- = C(SH)- C(SH )-C(O)(1-aza-18-crown-6)] was studied at therapeutic relevant radioactive concentrations. The results were compared with 188Re-MAG3 (MAG3: mercaptoacetyltriglycine) and 188Re-DMSA preparations (DMSA: dimercaptosuccinic acid) performed with the same highly concentrated [188Re]perrhenate solution (12-15 GBq/ml). Methods: The 188Re complexes were prepared by direct reduction of perrhenate (188Re-S4-complex) as well as via the 188Re-EDTA precursor complex (188Re-MAG3, 188Re-DMSA). The preparations were stabilised with 15 mg of ascorbic acid and analysed after 1, 2, and 24 hours by TLC and HPLC. Additionally, in vitro and in vivo stability studies were performed with the purified complexes. Results: After stabilisation with 15 mg of ascorbic acid, all of the complexes were nearly stable under nitrogen for hours, and only 2-8% of perrhenate was observed after 24 h. In contrast, only the 188Re-S4 complex was completely stable in vitro and in all investigated in vivo samples after separation of ligand excess and reducing agent by HPLC. Conclusion: The bridging amine group or free carboxylic groups of the S4-ligand framework make available reactive positions for coupling biomolecules to the chelate. Thus it appears that the new 188Re-S4 complexes offer the possibility of stable and high specific activity labelling of biomolecules for therapeutic application. (orig.)