First-Generation Bispidine Chelators for 213BiIII Radiopharmaceutical Applications

Hepta- and octadentate bispidines (3,7-diazabicyclo[3.3.1]nonane, diazaadamantane) with acetate, methyl-pyridine and methyl-picolinate pendant groups at the amine donors of the bispidine platform have been prepared and used to investigate their BiIII coordination chemistry. Crystal structural 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 BiIII and in all cases forms 9-coordinate complexes, and 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 213BiIII based radiopharmaceuticals. However, the two isomeric picolinate-/acetate-based heptadentate ligands already show very efficient complexation kinetics with 213BiIII at ambient temperature and kinetic stability that is comparable with the standard ligands used in this field. The experimentally determined hydrophilicities (log D7.4 values) show that the BiIII complexes reported are relatively hydrophilic and well suited for medicinal applications, and 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.

BRUCHERTSEIFER Frank;  COMBA Peter;  MARTIN Bodo;  MORGENSTERN Alfred;  NOTNI Johannes;  STARKE Miriam;  WADEPOHL Hubert; 

2020-10-20

WILEY-V C H VERLAG GMBH

JRC120441

1860-7179 (online),   

https://publications.jrc.ec.europa.eu/repository/handle/JRC120441,   

10.1002/cmdc.202000361 (online),