Terpyridine-Based Heteroditopic Ligand for Ru II Ln 3 III Metallostar Architectures (Ln = Gd, Eu, Nd, Yb) with MRI/Optical or Dual-Optical Responses Alexandre Boulay, †,‡ Ce ́ line Deraeve, †,‡,# Luce Vander Elst,* ,§,∥ Nadine Leygue, †,‡ Olivier Maury, ⊥ Sophie Laurent, §,∥ Robert N. Muller, §,∥ Be ́ atrice Mestre-Voegtle ́ ,* ,†,‡ and Claude Picard* ,†,‡ † CNRS, Laboratoire de Synthe ̀ se et Physico-Chimie de Mole ́ cules d’Inte ́ rê t Biologique, SPCMIB, UMR-5068, 118 Route de Narbonne, F-31062 Toulouse cedex 9, France ‡ Universite ́ de Toulouse, UPS, Laboratoire de Synthe ̀ se et Physico-Chimie de Molé cules d’Inté rê t Biologique, SPCMIB, 118 route de Narbonne, F-31062 Toulouse cedex 9, France § NMR and Molecular Imaging Laboratory, Department of General, Organic and Biomedical Chemistry, University of Mons, 23 Place du Parc, B-7000 Mons, Belgium ∥ Center for Microscopy and Molecular Imaging (CMMI), Rue Adrienne Bolland, 8, B-6041 Gosselies, Belgium ⊥ Universite ́ de Lyon 1, Laboratoire de Chimie de l’ENS Lyon, CNRS UMR 5182, 46 allé ed’Italie, 69364 Lyon, France * S Supporting Information ABSTRACT: A new ditopic ligand (L) based on a 2,2′:5′,4″- terpyridine unit substituted in the 2″,6″ positions with iminodiace- tate arms has been designed and synthesized for the construction of Ru II L 3 Ln 3 III supramolecular architectures. The two components of this system, a 2,2′-bipyridine unit for Ru II coordination and a pyridine-bis(iminodiacetate) core for Ln III coordination, are tightly connected via a covalent C arom (py)−C arom (py) bond. The para- magnetic and photophysical properties of the corresponding tetrametallic Ru II L 3 Gd 3 III complex have been evaluated, highlighting the potential of this metallostar structure to act as a bimodal MRI/ optical imaging agent. Variable-temperature 17 O NMR and proton nuclear magnetic relaxation dispersion (NMRD) measurements showed that this complex exhibits (i) a remarkable relaxivity per metallostar molecule, particularly at clinical and high magnetic fields (r 1 310K = 51.0 and 36.0 mM −1 s −1 at 20 and 300 MHz, respectively) and (ii) a near-optimal residence lifetime of Gd III coordinated water molecule (τ M 310K = 77.5 ns). This is the result of the presence of two inner-sphere water molecules in the Gd III components of the metallostar and a slow tumbling rate of the molecule (τ R 310K = 252 ps). Upon excitation in the visible domain (λ exc = 472 nm), the Ru II component of the complex exhibits a bright-red luminescence centered at 660 nm with a quantum yield of 2.6% in aqueous solutions at pH 7.4. Moreover, this Ru II L 3 Gd 3 III assembly is also characterized by a high kinetic inertness in biological media (PBS and human serum solutions) and a high photostability (photobleaching). Finally, preliminary photophysical studies on RuL 3 Nd 3 and RuL 3 Yb 3 assemblies revealed that the Ru II center acts as an effective sensitizer for Ln III -based luminescence in the near-IR region. The Nd III species was found to be the most effective at quenching the 3 MLCT luminescence of the Ru center. ■ INTRODUCTION In MRI domains, the use of gadolinium(III) contrast agents (CAs), commonly called T 1 or positive agents because they increase signal intensity, is well-established, and, currently, intensive research efforts are devoted to the design of more efficient Gd III -based CAs. 1−4 In addition to their main applications in clinical diagnosis (∼30−40% MRI exams), they are also used in medical research and pharmacogical studies including in vitro and animal experiments. 5 The contrast efficiency, named relaxivity and symbolized by r 1 , of Gd III -based CAs currently in clinical use is relatively low (r 1 ≈ 4 mM −1 s −1 at 20 MHz and 37 °C). 6 This implies the use of high concentrations (0.1 mM kg −1 total body weight) of these CAs, which does not limit them as bulk extracellular relaxation agents but becomes a severe limitation for their use as molecular MRI agents. 7 In this latter emerging MRI domain, a high relaxivity concentrated into a limited molecular volume is required for selected biological targets or specific cellular events. The more straightforward and simplest procedure to allow a marked sensitivity enhancement deals with the use of architectures containing several Gd III chelating units of sufficient relaxivity. Such systems concentrate several MRI probes in a small volume, but they may also enhance the Received: September 30, 2014 Published: January 16, 2015 Article pubs.acs.org/IC © 2015 American Chemical Society 1414 DOI: 10.1021/ic502342x Inorg. Chem. 2015, 54, 1414−1425