title: Calix[4]arenes as molecular platforms for magnetic resonance imaging (MRI) contrast agents.
abstract: The novel amphipilic conjugate of a calix[4]arene with four Gd-1,4,7,10- tetra(carboxymethyl)-1,4,7,10-tetraazacyclododecane (DOTA) chelates has potential as a magnetic resonance imaging contrast agent, both in its monomeric and in its micellar form. The system, illustrated here with its nuclear magnetic relaxation profile, shows good relaxivities, thanks to its high rigidity.An amphiphilic conjugate 1 of a calix[4]arene with four Gd-DOTA chelates (DOTA=1,4,7,10-tetra(carboxymethyl)-1,4,7,10-tetraazacyclododecane) was prepared and the properties relevant to its application as a magnetic resonance imaging (MRI) contrast agent were investigated by NMR, dynamic light scattering (DLS), and cryo-electron microscopy (cryo-TEM). The compound aggregates in water; its critical micelle concentration (cmc) is 0.21 mM (or 0.84 mM for Gd) at 37 degrees C. The relaxivity of the aggregates at 37 degrees C and 20 MHz (18.3 s(-1) per mM Gd or 73.2 s(-1) per mM 1) is about twice that of the monomer. Nuclear magnetic relaxation dispersion (NMRD) profiles show the relaxivity of the monomer to be almost independent of the magnetic field strength up to 60 MHz. At higher concentrations, the NMRD profiles exhibit a maximum at about 20 MHz, which is typical for high molecular volumes. The average water residence lifetime is 1.20 mus at 298 K as determined by (17)O NMR. The rotational correlation time of the monomer (390 ns at 37 degrees C) is very close to the optimal value predicted for high-field contrast agents. Monomer as well as micelles are very rigid systems with negligible local contributions to the overall rotational dynamics. The binding to human serum albumin (HSA) is significant (K(A)=1.2x10(3) M(-1)) and the relaxivity of the HSA adduct at 20 MHz is 24.6 s(-1) per mM Gd or 98.5 s(-1) per mM 1.
authors.affiliation: Department of Biotechnology, Biocatalysis and Organic Chemistry, Delft University of Technology, Julianalaan 136, 2628 BL Delft, The Netherlands.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Schühle
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schatz
authors.forename: Sophie
authors.initials: S
authors.lastname: Laurent
authors.forename: Luce
authors.initials: L
authors.lastname: Vander Elst
authors.forename: Robert N
authors.initials: RN
authors.lastname: Muller
authors.forename: Marc C A
authors.initials: MC
authors.lastname: Stuart
authors.forename: Joop A
authors.initials: JA
authors.lastname: Peters
mesh_terms: D000465:Algorithms; D047250:Calixarenes / Q000737:chemistry*; D005682:Gadolinium / Q000737:chemistry*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008823:Micelles; D008956:Models, Chemical; D009942:Organometallic Compounds / Q000737:chemistry*; D009943:Organophosphorus Compounds / Q000737:chemistry*; D010636:Phenols / Q000737:chemistry*; D012709:Serum Albumin / Q000737:chemistry
chemical_list: D008823:Micelles; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; D010636:Phenols; D012709:Serum Albumin; C121325:calix(4)arene; C059412:gadolinium-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetrakis(methylenephosphonic acid); D047250:Calixarenes; D005682:Gadolinium