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First‐Generation Bispidine Chelators for 213 Bi III Radiopharmaceutical Applications
Author(s) -
Bruchertseifer Frank,
Comba Peter,
Martin Bodo,
Morgenstern Alfred,
Notni Johannes,
Starke Miriam,
Wadepohl Hubert
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000361
Subject(s) - bifunctional , chemistry , nonane , chelation , adamantane , pyridine , carboxylate , mass spectrometry , amine gas treating , chemical stability , crystallography , computational chemistry , stereochemistry , inorganic chemistry , organic chemistry , catalysis , chromatography
Hepta‐ and octadentate bispidines (3,7‐diazabicyclo[3.3.1]nonane, diaza‐adamantane) with acetate, methyl‐pyridine, and methyl‐picolinate pendant groups at the amine donors of the bispidine platform have been prepared and used to investigate Bi III coordination chemistry. Crystal structure and solution spectroscopic data (NMR spectroscopy and mass spectrometry) confirm that the rigid and relatively large bispidine cavity with an axially distorted geometry is well suited for Bi III and in all cases forms nine‐coordinate complexes; this is supported by an established hole size and shape analysis. It follows that nonadentate bispidines probably will be more suited as bifunctional chelators for 213 Bi III ‐based radiopharmaceuticals. However, two isomeric picolinate‐/acetate‐based heptadentate ligands already show very efficient complexation kinetics with 213 Bi III at ambient temperature and kinetic stability that is comparable with the standard ligands used in this field. The experimentally determined hydrophilicities (log D 7.4 values) show that the Bi III complexes reported are relatively hydrophilic and well suited for medicinal applications. We also present a very efficient and relatively accurate method to compute charge distributions and hydrophilicities, and this will help to further optimize the systems reported here.