Chiral DOTA chelators as an improved platform for biomedical imaging and therapy applications

Lixiong Dai,Tiffany A Pham,Ga-Lai Law,Chloe M Jones,Wesley Ting Kwok Chan,Xiaoxi Ling,Nicholas J Rotile,Carolyn J Anderson,William Chi-Shing Tai,Peter Caravan,Eric M Gale

doi:10.1038/s41467-018-03315-8

Abstract

Despite established clinical utilisation, there is an increasing need for safer, more inert gadolinium-based contrast agents, and for chelators that react rapidly with radiometals. Here we report the syntheses of a series of chiral DOTA chelators and their corresponding metal complexes and reveal properties that transcend the parent DOTA compound. We incorporated symmetrical chiral substituents around the tetraaza ring, imparting enhanced rigidity to the DOTA cavity, enabling control over the range of stereoisomers of the lanthanide complexes. The Gd chiral DOTA complexes are shown to be orders of magnitude more inert to Gd release than [GdDOTA]−. These compounds also exhibit very-fast water exchange rates in an optimal range for high field imaging. Radiolabeling studies with (Cu-64/Lu-177) also demonstrate faster labelling properties. These chiral DOTA chelators are alternative general platforms for the development of stable, high relaxivity contrast agents, and for radiometal complexes used for imaging and/or therapy.

Highlights

All chemicals were of reagent-grade and were purchased from Sigma-Aldrich or Acros Organics and used without further purification, (2 S)-1-Benzyl-2-ethylaziridine, (S)-1-benzyl-2isobutylaziridine and (S)-1,2-dibenzylaziridine were ordered from Beijing Peridachem Co., Ltd. 1H and 13C NMR spectra were recorded on a Bruker Ultrashield 400 Plus NMR spectrometer or a Bruker Ultrashield 600 Plus NMR spectrometer
The method used on this system is as follows: Restek ultraaqueous C18 column (100 × 4.6 mm); eluent A: 10 mM ammonium acetate in water, B: 90% acetonitrile/10% 10 mM ammonium acetate in water; gradient: 5% B was held for 2 min before increasing the fraction of B to 50% over 10 min
The column was washed with 95% B for 2 min and ramped to 5% B

Summary

Introduction

The method used for purification is as follows: starting from 95% A/5% B, the fraction of B increased to 50% over 23 min. The mobile phase A was water with 10 mM ammonium formate added; mobile phase B was 90% acetonitrile/10% water with 10 mM ammonium formate added; The method used for purification is as follows: starting from 95% A/5% B, the fraction of B increased to 50% over 23 min.

Results

Conclusion