Highly stable acyclic bifunctional chelator for ⁶⁴Cu PET imaging

Abstract

Ligand L 1 , based on a pyridine scaffold, functionalized by two bis(methane phosphonate)aminomethyl groups, was shown to display a very high affinity towards Cu(II) (log K CuL = 22.7) and selectivity over Ni(II), Co(II), Zn(II) and Ga(III) (Δ log K ML > 4) as shown by the values of the stability constants obtained from potentiometric measurements. Insights into the coordination mode of the ligand around Cu(II) cation were obtained by UV-Vis absorption and EPR spectroscopies as well as density functional theory (DFT) calculations (B3LYP model) performed in aqueous solution. The results point to a pentacoordination pattern of the metal ion in the fully deprotonated [CuL 1 ] 6− species. Considering the beneficial thermodynamic parameters of this ligand, kinetic experiments were run to follow the formation of the copper(II) complexes, indicating a very rapid formation of the complex, appropriate for 64 Cu complexation. As L 1 represents a particularly interesting target within the frame of 64 Cu PET imaging, a synthetic protocol was developed to introduce a labeling function on the pyridyl moiety of L 1 , thereby affording L 2 , a potential bifunctional chelator (BFC) for PET imaging.

Phosphonated chelates for nuclear imaging

“…12 The sequence of LM stability constants (Table 3) is indeed in agreement with the Irving-Williams series which defines that the classical thermodynamic order for transition-metal complexes is Mn(II) < Fe(II) < Co(II) < Ni(II) < Cu(II) > Zn(II). This binding selectivity also exists for other polyaminomethanephosphonate ligands such as DO2P.…”

“…The complexation should be efficient and rapid at room temperature and at low concentration, at a pH suitable for biological applications. 11,12 We have also shown that L 1 can be derivatized into an activated phosphonated bifunctional chelate L* (Scheme 1) which can be coupled to small peptides or large antibodies. [8][9][10][11][12][13][14][15][16] With phosphonated ligands, the thermodynamic stability constants of the Cu(II) complexes are notably higher than those of their acetate analogues.…”

“…2,5,6 Although these radionuclides can be used for their intrinsic properties, as in the case of thyroid imaging with 99m TcO 4 − , 7 the applications of 64 Cu and 99m Tc as targeted radiopharmaceuticals generally require the use of bifunctional chelates (BFC) designed to selectively bind the radionuclide and to be covalently linked to a bio-targeting vector such as an antibody, a peptide or a protein. [8][9][10][11][12][13][14][15][16] With phosphonated ligands, the thermodynamic stability constants of the Cu(II) complexes are notably higher than those of their acetate analogues. The complexation should be efficient and rapid at room temperature and at low concentration, at a pH suitable for biological applications.…”

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

“…L 2 showed one band, centered at 263 nm, attributed to the π-π* transition of the pyridine rings, which underwent a hypochromic variation with the appearance of shoulders upon increase of the pH. 60 The statistical analysis of the potentiometric and spectrophotometric data versus pH was achieved with Hyperquad2008 85 and Hypspec softwares, 78 respectively, and led to the determination of five protonation constants of ligand L 2 in the pH range from -0.59 to 11.93 (Table 4). The first protonation constant (log K 1 H =11.5(3)) was assigned to the tertiary amine of the bispidine skeleton.…”

Importance of Outer‐Sphere and Aggregation Phenomena in the Relaxation Properties of Phosphonated Gadolinium Complexes with Potential Applications as MRI Contrast Agents

“…[12] Within the frame of our search for highly efficient complexes for molecular imaging, we have been interested in the design of polyphosphonated chelates for luminescence, [7,13] or radiochemicala pplications. [14] In this study,w er eport on the coordination behavior of as eries of bis-,t ris-and tetraphosphonated ligands( Scheme 1) with lanthanide cations and we particularly inspect the influence of the number of phosphonic coordinating units on the relaxation properties of the corresponding Gd III chelates.…”