Bifunctional Gd(III) and Tb(III) chelates based on a pyridine–bis(iminodiacetate) platform, suitable optical probes and contrast agents for magnetic resonance imaging

Abstract

To study the physicochemical properties of lanthanide complexes derived from a bifunctional chelating agent based on a PMN-tetraacetic acid moiety {PMN-tetraacetic acid (1): [2,6-pyridinediylbis(methylene nitrilo)-tetraacetic acid]}, 4-carboxylic acid substituted pyridine derivative (2) was synthesized. This ligand forms heptadentate (N3 O4 ) Ln(III) complexes (Ln = Gd, Eu, Tb), with two water molecules completing the inner coordination sphere of the metal. The parameters that govern the relaxivity of the Gd(III) complex and the luminescence of Eu(III) and Tb(III) complexes were obtained by (17) O and (1) H NMR studies and time-resolved fluorescence experiments, respectively. The gadolinium and terbium complexes show interesting properties either for MRI or FOR optical imaging; that is, for the Gd complex, a high proton relaxivity (r1 = 6.4 s(-1) mM(-1) at 20 MHz) with short water residence time (τM = 38.5 ns); for the Tb complex, a luminescence lifetime of 1.22 ms at room temperature and a luminescence quantum yield of 10%. The kinetic stability of these complexes toward blood protein, cation or bioactive oxyanion was also examined. The Gd(2)(H2O)2 complex does not interact with human serum albumin, but undergoes a transmetalation reaction with Zn(II) in a phosphate buffer solution (pH 7.4), rather similar to that of Gd-DTPA-BMA(H2 O). On the other hand, as observed for Eu and Tb complexes, these chelates do not form ternary complexes with bidentate anions such as l-lactate, citrate or carbonate. Finally, a phosphatidylserine-specific hexapeptide (TLVSSL) was grafted on Gd or Tb chelates, and the Gd-peptide conjugate was used in vitro for targeting apoptotic cells.

Structures, and luminescence and magnetic properties of Ln(III) complexes bearing dibenzoylmethane ligand (Ln=Eu and Gd)

“…In particular, the unquenched orbital moment of Eu(III) with the 7 F 0 ground state can give rise to fascinating magnetic properties associated with its anisotropy. Therefore, Ln(III) complexes may be applicable to the in vivo contrast imaging and luminescent probes [19][20][21][22][23][24]. To date, the magnetic properties of the Ln(III) complexes with homoleptic DBM, and mixed DBM and phen have not been reported.…”

Recent Advances in Bifunctional Paramagnetic Chelates for MRI

“…Compound 19 was attached via Michael addition to the thiol group of the cysteine residue in peptides with the aim to perform, on the corresponding Gd(III)‐complex, some distance measurement by electron paramagnetic resonance spectroscopy (EPR) . Gadolinium complex of 20 was coupled in a classical way by means of EDCI to a phosphatidylserine‐specific hexapeptide (TLVSSL) to study the in vitro targeting of apoptotic cells …”

1H‐NMR relaxometric studies of interaction between apoptosis specific MRI paramagnetic contrast agents and micellar models of apoptotic cells

“…For solutions in presence of micelles, the Lipari-Szabo model was used. [32,33] Gd-complexes synthesis [18,19] Gadolinium chelates are grafted on the N-terminal part of the peptide coupled to a linker. Indeed, activation of the carboxyl function at position 4 of pyridine of the gadolinium chelate (gadolinium 2,2′,2′′,2′′′-[((4-carboxy)pyridine-2,6-diyl)bis(methylenenitrilo)]-tetrakis acetate was obtained in situ with EDCI HCl (EDCI HCl= 1-ethyl-3(3dimethylaminopropyl) carbodi-imide hydrochloride)) in a solution containing NHS À3-sulfonic acid (NHS = N-hydroxysuccinimide).…”

“…Kapty et al [23] radiolabeled R826 peptide with 18 In the present study, we used phospholipidic micellar models to simulate apoptosis like in our previous report on the E3 and R826 peptides. [24] Micelles are indeed well known to mimic biological membranes in various fields (e.g.…”

“…One of the challenges of our laboratory is the vectorization of MRI contrast agents in order to target a disease via, for example, a peptide or a specific molecule . Because PS is a hallmark for apoptosis, we grafted two hexapeptides already selected for targeting PS and called E3 and R826 to chelates of gadolinium (Gd‐PMN‐E3 and Gd‐DTPA‐R826, respectively, Fig. ).…”