La-[^18/19F]fluoride complexes: a novel addition to the radiofluorination family

Here, we report the synthesis and evaluation of La-[^18/19F]fluoride coordination complexes with macrocyclic ligands, expanding the family of metal-[¹⁸F]fluoride coordination species for PET imaging applications. Fluorination of a series of La complexes with macrocyclic chelators (L = DOTA, DOTAM, macropa, and DOTpy) was explored, and the resulting products were characterized using ¹⁹F and ¹H NMR, mass spectrometry, and X-ray spectroscopy. The stability of these complexes in water was found to inversely correlate with the electron-donating properties of the chelator. Notably, [LaF(L)]^x complexes with macropa and DOTpy exhibited high stability in organic solution, with [LaF(DOTpy)]OTf₂ also demonstrating stability in water. DFT study (PBE-D3(BJ)/TZ2P, COSMO) indicates that the ΔΔG magnitudes between [LaFL] and [La(H₂O)L] could explain these results: much higher for DOTpy (21.66 kcal mol^-1) and DOTAM (15.86 kcal mol^-1) than for DOTA (6.78 kcal mol^-1) and Macropa (8.05 kcal mol^-1) supports the observed stabilities. Radiofluorination of [LaF(DOTpy)]OTf₂ afforded [¹⁸F][LaF(DOTpy)]²⁺ in high radiochemical purity, representing the first example of a La-[¹⁸F]fluoride coordination complex. These findings expand the scope of metal-[¹⁸F]fluoride coordination chemistry and lay the groundwork for developing La/Ac-based fluoride complexes as theranostic pairs, with applications in ²²⁵Ac-based radiopharmaceuticals for personalized dosimetry and PET-guided therapy monitoring.