Towards ²¹³Bi alpha-therapeutics and beyond: unravelling the foundations of efficient Bi^III complexation by DOTP

Abstract

Bismuth isotopes are attracting an increasing attention for their potential applications in diagnostics and therapy. The emerging use of 213Bi in targeted α-therapy (TAT) is a particularly relevant example because...

Chelating the Alpha Therapy Radionuclides 225Ac3+ and 213Bi3+ with 18-Membered Macrocyclic Ligands Macrodipa and Py-Macrodipa

“…Although the lability of Ac 3+ −py-macrodipa precludes its use with 225 Ac 3+ in nuclear medicine, the efficient formation and high stability of Bi 3+ −py-macrodipa, which surpasses Bi 3+ −macropa, suggests that this ligand is a valuable candidate for 213 Bi 3+ chelation. These results highlight that py-macrodipa joins other promising candidates for 213 Bi 3+ chelation that have arisen in recent years. ,− Ongoing work is directed toward the synthesis of a bifunctional analogue of py-macrodipa to apply this chelator in TAT, as well as the development of “macrodipa-type” chelators with enhanced Ac 3+ complex stabilities.…”

The Evolving Coordination Chemistry of Radiometals for Targeted Alpha Therapy

“…NMR spectroscopy indicated that the complex interconverts between the two enantiomeric pairs in solution. [89] The [Bi(DOTP)] 5complex was shown to have a formation constant of 10 38.7 and significant kinetic inertness (t 1/2 , pH 3 ¼ 47000 h). [89] H 8 DOTP displayed an impressive ability to achieve 213 Bi radiolabelling efficiencies of ,90 % at RT and ligand concentrations of 10 À4 M that was comparable with CHX-A-DTPA under the same conditions.…”

“…[89] The [Bi(DOTP)] 5complex was shown to have a formation constant of 10 38.7 and significant kinetic inertness (t 1/2 , pH 3 ¼ 47000 h). [89] H 8 DOTP displayed an impressive ability to achieve 213 Bi radiolabelling efficiencies of ,90 % at RT and ligand concentrations of 10 À4 M that was comparable with CHX-A-DTPA under the same conditions. [87] Comparison stability studies showed that [ 213 Bi][Bi(H 4 DOTP)]was more stable than [ 213 Bi][Bi(DOTA)]and [ 213 Bi][Bi(CHX-A-DTPA)] 2in both human plasma and to an excess of DTPA 5over 3 h. The faster formation kinetics could be due to the affinity of the Bi 3þ ion for phosphonate oxygen atoms and/or the orientation of the phosphonate groups (two above and two away from the ring N atoms), which is in contrast to H 4 DOTA, where all four carboxylates are positioned above the plane of the ring N atoms.…”

“…8). [95] The Radiolabelling conditions E Bioconjugate Acyclic H 5 DTPA [81] N 3 O 5 Monocapped square antiprism 35.6 60 A H 5 CHX-A-DTPA [82] N 3 O 5 Square antiprism/dodecahedron 34.9-35.6 94 B RT, pH 5, 5 min, 10 À4 M HuM195; [83] B72.3 [79] Bispidines H 2 bispa 2 [84] N 6 O 2 RT, pH 5, 5 min, 10 À7 M Cyclen-based H 4 DOTA [85][86][87] N 4 O 4 Twisted square antiprism 30.3 85 C 958C, pH 5.5, 5 min, 10 À4 M RT, pH 5.5, 5 min, 10 À4 M F Octreotide PSMA-617 H 8 DOTP [87][88][89] N 4 O 4 Twisted square antiprism 38.7 96 C RT, pH 5, 5 min,10 À4 M Lpy [90] N 8 RT, pH 6.8, 5 min 10 À4 M G H 2 MeDodpa [91] N 6 O 2 Twisted square antiprism 34.2 90 D 908C, pH 7.4, 15 min H 2 semicarbazone [92] N 6 O 2 Twisted square antiprism 95 D 958C, pH 8.5, 5 min, 10 À3 M 18-Crown-6-based H 2 macropa [85] N 4 O 6 Pentagonal pyramid RT, pH 5.5, 8 min, 10 À6 M H 2 macropaquin [85] N 4 O 6 RT, pH 5.5, 8 min, 10 À6 M H 2 macropaquin-SO 3 enantiomers. NMR spectroscopy indicated that the complex interconverts between the two enantiomeric pairs in solution.…”

Boosting Bismuth(III) Complexation for Targeted α‐Therapy (TAT) Applications with the Mesocyclic Chelating Agent AAZTA**

“…These conditions are hardly compatible with the preparation of labile bioconjugates and detrimental in terms of residual radio-activity, taking a time comparable to one half-life of 213 Bi. [9,10] The variation of the pendant arms of the macrocyclic CAs was demonstrated to be a possible strategy to speed up the formation kinetics of Bi III -complexes. [11] The phosphonate analogue DOTP was recently shown to combine a higher thermodynamic stability with a faster complexation kinetics with respect to the carboxylic counterpart.…”