Thermodynamic evaluation of the stability of the bone-seeking radiopharmaceutical [177Lu]Lu(III)–DOTP under simulated blood plasma conditions

The stability and in vivo robustness of [177Lu]Lu–DOTP as a potential bone-targeting radiopharmaceutical was determined with the aid of thermodynamic blood plasma modeling simulations. Glass electrode potentiometry was employed to measure the stability constants of the complexes of Lu3+ with DOTP. Similarly, the complexes of DOTP with a selection of the important physiological metal ions: Ca2+, Mg2+, and Cu2+ were determined, representing the typical interactions that the ligand would encounter upon administration. This made possible the construction of a blood plasma model of DOTP, aiding in establishing the potential susceptibility of the radiopharmaceutical. The ligand binds predominantly to calcium in vivo, accounting for 59.6% of that initially introduced as a component of the Lu–DOTP complex. Furthermore, due to a preference of the DOTP to bind to Cu2+ it causes mobilization of the ions in blood plasma, and would therefore indicate a deficiency if the ligand is administered at a concentration of 8.5 × 10−5 mol dm−3. The lutetium-ions are preferentially bound to DOTP, with as much as 98.1% of the Lu3+ occupying the ligand under physiological conditions.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Thermodynamic blood plasma model supports in vivo biodistribution of [177Lu]Lu–DOTP. ► Lu3+ remains predominantly complexed (98.1%) with the DOTP under simulated physiological conditions. ► Thermodynamic and kinetic stability [177Lu]Lu–DOTP in blood plasma facilitates selectivity of the proposed radiopharmaceutical for bone.