Ln[DO3A-N-α-(pyrenebutanamido)propionate] complexes: optimized relaxivity and NIR optical properties†

We have proposed recently that the DO3A-N-α-(amino)propionate chelator and its amide conjugates are leads to targeted, high relaxivity, safe contrast agents for magnetic resonance imaging. In this work we illustrate further the expeditious nature and robustness of the synthetic methodologies developed by preparing the DO3A-N-(α-pyrenebutanamido)propionate chelator. Its Gd3+ chelate retains the optimized water exchange, high stability and inertness of the parent complex. The pyrene moiety imparts concentration- dependent self-assembly properties and aggregation-sensitive fluorescence emission to the Gd3+ complex. The Gd3+ complex displays pyrene-centred fluorescence whilst the Yb3+ and Nd3+ complexes exhibit sensitized lanthanide-centred near-infrared luminescence. The aggregated form of the complex displays high relaxivity (32 mM−1 s−1, 20 MHz, 25 °C) thanks to simultaneous optimization of the rotational correlation time and of the water exchange rate. The relaxivity is however still limited by chelate flexibility. This report demonstrates that the DO3A-N-(α-amino)propionate chelator is a valuable platform for constructing high relaxivity CA using simple design principles and robust chemistries accessible to most chemistry labs.This work was financially supported by Fundação para a Ciência e Tecnologia, Portugal: project PTDC/QUI/70063/2006, including a grant to C.I.O.M., grant SFRH/BD/63994/2009 to M.F.F., grant SFRH/BD/46370/2008 to A.F.M. and sabbatical grant SFRH/BSAB/ 1328/2013 to J.A.M. and Rede Nacional de RMN (REDE/1517/RMN/2005) for the acquisition of the Varian VNMRS 600 NMR spectrometer in Coimbra. The work in France was supported by La Ligue contre le Cancer. This work was carried out in the framework of the COST Actions D38 “Metal Based Systems for Molecular Imaging”, TD1004 “Theragnostic Imaging” and CM1006 “EUFEN: European F-Element Network”. S.P. acknowledges support from the Institut National de la Santé et de la Recherche Médicale (INSERM)