Structural Variations in Carboxylated Bispidine Ligands: Influence of Positional Isomerism and Rigidity on the Conformation, Stability, Inertness and Relaxivity of their Mn²⁺ Complexes

Abstract

Mn2+ complexes of 2,4‐pyridyl‐disubstituted bispidine ligands have emerged as more biocompatible alternatives to Gd3+‐based MRI probes. They display relaxivities comparable to that of commercial contrast agents and high kinetic inertness, unprecedented for Mn2+ complexes. The chemical structure, in particular the substituents on the two macrocyclic nitrogens N3 and N7, are decisive for the conformation of the Mn2+ complexes, and this will in turn determine their thermodynamic, kinetic and relaxation properties. We describe the synthesis of four ligands with acetate substituents in positions N3, N7 or both. We evidence that the bispidine conformation is dependent on N3 substitution, with direct impact on the thermodynamic stability, kinetic inertness, hydration state and relaxivity of the Mn2+ complexes. These results unambiguously show that (i) solely a chair‐chair conformation allows for favorable inertness and relaxivity, and (ii) in this family such chair‐chair conformation is accessible only for ligands without N3‐appended carboxylates.

Bispidine Chelators for Radiopharmaceutical Applications with Lanthanide, Actinide, and Main Group Metal Ions

“…The first protonation at a pK a value of 11.31 corresponds to the protonation of one of the tertiary amines of the bispidine backbone, while the other remains protonated in the accessible pH range. 32,34,36 Scheme 2. Synthetic Route to L 3 The next pK a values can be attributed to the protonation of the nitrogen donors at the pyridine groups (pK a = 7.57), the nitrogen of the picolinic acid (pK a = 4.58), and the carboxylic acid of the picolinic acid group (pK a = 3.30).…”

“…Even with Pb 2+ , the titration with L 3 is less efficient than with L 2 ; full reproducibility of the titration data was secured by longer than usual equilibration times (15 min). The first protonation at a p K a value of 11.31 corresponds to the protonation of one of the tertiary amines of the bispidine backbone, while the other remains protonated in the accessible pH range. ,, The next p K a values can be attributed to the protonation of the nitrogen donors at the pyridine groups (p K a = 7.57), the nitrogen of the picolinic acid (p K a = 4.58), and the carboxylic acid of the picolinic acid group (p K a = 3.30). On the basis of the titrations of the ligands, the distributions of various ligand species at different pH values are obtained (see panels a and b of Figure for L 2 and L 3 , respectively).…”

[52Mn]Mn-BPPA-Trastuzumab: A Promising HER2-Specific PET Radiotracer

“…In the past 8–10 years, several ligands have been identified as possible Mn(II) binders, forming stable and inert complexes with Mn(II). The best performing chelators ( trans- CDTA, PyC3A, PhDTA, 1,4-DO2A , and its amide derivatives, − 3,9-PC2A, PC2A-BP, OPC2A), and chelators possessing bispidine “backbone” − (Chart ) represent the structural rigidity necessary to achieve inertness. However, the use of [ 52 Mn]Mn-labeled agents in PET imaging is relatively new, with limited published research on the topic. − The ligands applied in these studies are either BFCs derived from DOTA (DOTA-GA-bevacizumab, p-SCN-Bn-DOTA) or 3,9-PC2ABn pCOOH . − …”

N^N^C-Cyclometalated rhodium(iii) complexes with isomeric pyrimidine-based ligands: unveiling the impact of isomerism on structural motifs, luminescence and cytotoxicity

“…Despite various kinds of constitutional and configurational isomerism of metal complexes being well known, 40 ligand isomerism, which belongs to constitutional isomerism, is documented in literature to a considerably lesser extent than other types of the isomerism of complexes. 23,41–64…”