A Bispidol Chelator with a Phosphonate Pendant Arm: Synthesis, Cu(II) Complexation, and ⁶⁴Cu Labeling

Abstract

Here we present the synthesis and characterization of a new bispidine (3,7-diazabicyclo[3.3.1]nonane) ligand with N-methanephosphonate substituents (L). Its physicochemical properties in water, as well as those of the corresponding Cu(II) and Zn(II) complexes, have been evaluated by using UV-visible absorption spectroscopy, potentiometry, H andP NMR, and cyclic voltammetry. Radiolabeling experiments with Cu have been carried out, showing excellent radiolabeling properties. Quantitative complexation was achieved within 60 min under stoichiometric conditions, at room temperature and in the nanomolar concentration range. It was also demonstrated that the complexation occurred below pH 2. Properties have been compared to those of the analogue bispidol bearing a N-methanecarboxylate substituent (L). Although both systems meet the required criteria to be used as new chelator for Cu in terms of the kinetics of formation, thermodynamic stability, selectivity for Cu(II), and kinetic inertness regarding redox- or acid-assisted decomplexation processes, substitution of the carboxylic acid function by the phosphonic moiety is responsible for a significant increase in the thermodynamic stability of the Cu(II) complex (+2 log units for pCu) and also leads to an increase in the radiochemical yields withCu which is quantitative for L.

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“…The acido-basic properties (pKa) of ligands SK2, SK3 and SK4 and their affinity for metals were determined via potentiometric titrations (Cu 2+ , Zn 2+ ) and spectrophotometric titrations versus pH (Fe 3+ ). The potentiometric titrations were carried out in water ( I = 0.1 M NaClO 4 ), in accordance with a previously published procedure (Gillet et al 2017 ), using a 904 DMS Titrando automatic titrator system (Methrom AG; Herisau, Switzerland) with a 2-ml Dosino 800 burette driven by the TiAmo 2.5 software (Methrom AG; Herisau, Switzerland) and a combined glass electrode (6.0234.100; long life, Methrom AG; Herisau, Switzerland) filled with 0.1-M NaCl. The Fe 3+ complexes were already fully formed at pH 2 and could, therefore, not be studied via this technique.…”

“…The protonation constants of the ligands SK2, SK3 and SK4, and their stability constants with Fe 3+ , were determined by ultraviolet (UV)–visible spectrophotometric titrations versus pH, by simultaneously recording pH and UV–visible spectra using a Metrohm UV–visible spectrophotometer (Cary 60 model, Agilent). Between pH = − 0.5 and 2, the batch technique was used; while, classical titrations were carried out for pH values between 2 and 12, following a published procedure (Gillet et al 2017 ). The ionic strength was not fixed at pH < 1 in the batch titrations and no decomposition of the ligands was observed, even in strongly acidic conditions.…”

Evaluation of a Bispidine‐Based Chelator for Gallium‐68 and of the Porphyrin Conjugate as PET/PDT Theranostic Agent

“…However,b ased on previouso bservations with 64 Cu analogues, [53] promising resultsi nt erms of kinetic inertness were expected when using ab ispidine scaffold. This was indeed the case when assessed for radiochemicals tability against foetal bovines erum (FBS) no decomplexation was observed over 2hours incubation at 37 8C( Figure S5).…”

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“…The protonated forms of the ligands C6 and C9 (10 -3 M) and the stability constants (log β) of their complexes with Cu 2+ ([L]/[Cu 2+ ] ≈ 2.2, L = C6 or C9) were characterized by potentiometric titrations in water in accordance with a previously published procedure (Gillet et al 2017) using an automatic titrator system (904 DMS Titrino, Metrohm Limited, Switzerland) with a combined glass electrode (6.0234.100; Long Life, Metrohm Limited, Switzerland) filled with 0.1 M NaCl. The Fe 3+ complexes were already fully formed at pH 2 and could therefore not be studied via this technique.…”

“…The log K values of the ligands C6 and C9 and their stability constants with Cu 2+ and Fe 3+ were determined by ultraviolet (UV)-visible spectrophotometric titrations versus pH, by simultaneously recording pH and UV-visible spectra. Between p[H] = − 0.5 and p[H] = 2 (brackets indicate that the pH value was calculated) the batch technique was used, following a previously published procedure (Gillet et al 2017).…”