Design of porous self-assembled homoleptic and heteroleptic Pd2+ cages incorporating Silicon-based Fluoride Acceptors: the way towards nuclear imaging applications

Abstract

Supramolecular self-assembly is a promising tool to develop multifunctional theranostic agents and has recently entered the field of radiochemistry. In this work, lantern-shaped [Pd2L4]4+ metallacages featuring a blood-brain barrier-penetrating peptide were designed for dual-modality imaging. Two silicon-based fluoride acceptors were incorporated in the cage ligand for radiolabeling with Fluorine‑18, an isotope used in positron emission tomography (PET). Ligands (L1, L2) and the respective homoleptic cages (C1hom [Pd2(L1)4]4+, C2hom [Pd2(L2)4]4+) were fully characterized by NMR spectroscopy, liquid chromatography and high-resolution electrospray mass spectrometry (HR-ESI-MS). Cage stability was assessed in different solvents and concentrations by HPLC. 18F-labelled cages were obtained by radiolabeling the ligands pre-assembly under mild conditions within four hours via [19F]-to-[18F] isotopic exchange. The high lipophilicity of the ligands was also assessed in vitro (LogDpH7.4) and in ovo, using the chick chorioallantoic membrane (CAM) model. Furthermore, formation of host-guest complexes between the metallacages and perrhenate (ReO4-), the ‘cold’ surrogate of radioactive 99mTcO4- (used for single photon computed tomography, SPECT), could be detected by mass spectrometry, although the adduct did not sustain chromatographic separation. To improve stability of the supramolecular system, heteroleptic cages of general formula [Pd2(L)m(L0)n]4+ (m = 1, 2, n = 4-m) were synthesized by statistical self-assembly and separated by liquid chromatography in good yield. Overall, this study demonstrates the feasible adaptation of supramolecular principles to achieve innovative theranostic agents.