Towards Targeted MRI: New MRI Contrast Agents for Sialic Acid Detection Luca Frullano, [a, b] Jan Rohovec, [c] Silvio Aime, [d] Thomas Maschmeyer, [a, e] M. Isabel Prata, [f] J. J. Pedroso de Lima, [f] Carlos F. G. C. Geraldes, [g] and Joop A. Peters* [a] Introduction The excellent contrast and spatial resolution of the images obtainedbymagneticresonanceimaging(MRI),particularly those of soft tissues, have made this technique one of the fastest growing diagnostic methodologies. An MRI image is generated from the NMR resonance of water protons and the contrast depends essentially on three factors, 1)the water proton density, 2)the longitudinal relaxation time, T 1 , and 3)the transverse relaxation time, T 2 , of these pro- tons. [1–4] Paramagnetic contrast agents (CAs) are often ad- ministered prior to the scan to improve the contrast in the image. The role of these CAs, usually Gd 3 + complexes, is to shorten the relaxation times of the water 1 HNMR reso- [a] Dr.L.Frullano,Prof.Dr.T.Maschmeyer,Dr.J.A.Peters LaboratoryofAppliedOrganicChemistryandCatalysis Julianalaan136,2628BLDelft(TheNetherlands) Fax:(+ 31)15-278-4289 E-mail:j.a.peters@tnw.tudelft.nl [b] Dr.L.Frullano Chemistry Department Northwestern University Evanston, Illinois 60208-3113 (USA) [c] Dr.J.Rohovec DepartmentofChemistry UniversitaKarlova 12840 Prague (Czech Republic) [d] Prof.S.Aime DipartimentodiChimicaI.F.M. UniversitàdiTorino 10125Torino(Italy) [e] Prof.Dr.T.Maschmeyer SchoolofChemistry TheUniversityofSydney NSW2006(Australia) [f] Dr.M.I.Prata,Prof.Dr.J.J.P.deLima DepartmentofBiophysicsoftheFacultyofMedicine UniversityofCoimbra 3000Coimbra(Portugal) [g] Prof.Dr.C.F.G.C.Geraldes DepartamentodeCiÞnciaseTecnologicae Centro NeurociÞncias UniversidadedeCoimbra 3049Coimbra(Portugal) Abstract: Thedetectionofsialicacidin living systems is of importance for the diagnosis of several types of malignan- cy. We have designed and synthesized two new lanthanide ion ligands (L 1 and L 2 ) that are capable of molecular rec- ognition of sialic acid residues. The basic structure of these ligands consists of a DTPA-bisamide (DTPA, diethyl- enetriamine pentaacetic acid) whose amide moieties each bear both a bor- onic function for interaction with the diol groups in the side chain of sialic acid,andafunctionalgroupthatispos- itively charged at physiologic pH values and is designed to interact with the carboxylate anion of sialic acid. The relaxometric properties of the Gd 3 + complexes of these two ligands were evaluated. The relaxivity of the GdL 1 complex has a significant second- sphere contribution at pH values above the pK a of its phenylboronic acid moiety. The interaction of the Gd 3 + complexes of L 1 and L 2 with each of several saccharides was investigated by means of a competitive fluorescent assay. The results show that both com- plexes recognize sialic acid with good selectivity in the presence of other sugars. The adduct formed by GdL 2 with sialic acid has the higher condi- tional formation constant (50.43  4.61 m 1 at pH7.4). The ability of such complexes to recognize sialic acid was confirmed by the results of a study on the interaction of corresponding radio- labeled complexes ( 153 SmL 1 and 153 SmL 2 ) with C6 glioma rat cells. 153 SmL 2 in particular is retained on the cellsurfaceinsignificantamounts. Keywords: borates · carbohydrates · drug design · lanthanides · magnetic resonance imaging Chem. Eur. J. 2004, 10,5205–5217 DOI: 10.1002/chem.200400369 #2004Wiley-VCHVerlagGmbH&Co.KGaA,Weinheim 5205 FULL PAPER