Re-188 complexes with tetradentate S₄ ligands derived from MESO-DMSA for labeling of biomolecules

Introduction:

Various Tc and Re chelates are currently under investigation for stable labeling of biomolecules. Unfortunately, most of the ¹⁸⁸Re chelates degrade more rapidly than the ^99mTc analogues which is limiting the further development of rhenium-based therapeutic agents. To overcome this problem, we developed a tetradentate S₄ ligands derived from DMSA [1].

Experimental:

Labeling. To a kit vial, containing 5 mg oxalic acid, 5 mg γ-cyclodextrin, 5 mg ascorbic acid and 0.01 - 0.05 mg Sn-S4 complex, 1.0 ml of perrhenate eluate (50–500 MBq) was added. After heating at 50 °C for 60' the yield was 90 – 93% (HPLC and TLC). For stability and biodistribution studies the isomers were separated by semi-preparative HPLC. The identity of the species obtained was confirmed by comparison with the HPLC profiles of fully characterized reference ^185/187Re analogues.
Biodistribution: Male Wistar rats (5 – 6 weeks old), 0.5 ml of the ¹⁸⁸Re complex solution (0.5 MBq) was injected into the tail vein under slight ether anesthesia. After the injection, the rats were sacrificed by heart puncture 5 min and 60 min post injection.

Results and Discussion:

A kit formulation was developed which contains only microgram amounts of the S₄ ligand stabilized in the form of a stannous complex. Several isomers were separated by HPLC from the preparation solutions and characterized in vitro and in vivo. All of them were absolutely stable in rat and human plasma solutions. Challenge experiments with cysteine corroborated the high inertness of the isomers towards ligand exchange reactions. Samples of blood, intestine and urine of rats confirmed the high in vivo stability of the ¹⁸⁸Re complexes. Biodistribution studies resulted in a high uptake and fast clearance from the liver of the more lipophilic cis and trans isomers of complex I (logD_o/w 1.5 - 1.7), whereas the hydrophilic isomers of complex II (logD_o/w about -1.75) were preferentially excreted via the renal pathway. The low level of radioactivity in the stomach indicated good in vivo stability too.

Conclusion:

The ¹⁸⁸Re-S₄ complexes offer the possibility of stable and high specific activity labeling of biomolecules. Their charge and lipophilicity may be controled by various possibilities to introduce functional groups. The amine group of the bridging framework makes available a position for coupling biomolecules.

[1] S. Seifert et al., Bioconjugate Chem. 2006, 17, 1601-1606.