Amide conjugates of the DO3A‐N‐(α‐amino)propionate ligand: leads for stable, high relaxivity contrast agents for MRI?

Abstract

A novel synthetic methodology for preparing amide conjugates of the DO3A-N-(α-amino)propionate chelator is described, using the synthesis of the DO3A-N-(α-benzoylamido)propionate chelator as an illustrative example. The model Gd[DO3A-N-(α-benzoylamido)propionate] chelate displays accelerated water exchange, stability in a wide pH range and inertness towards transmetallation by Zn(2+). The Gd[DO3A-N-(α-benzoylamido)propionate] complex is mainly excreted via the kidneys, producing a significant increase in the kidney medulla/cortex enhancement ratio in MR images of Wistar rats, reflecting probably its higher lipophilicity compared with Gd(DTPA). The results presented suggest that Gd[DO3A-N-(α-amido)propionate] chelates can be valuable leads for preparing potentially safe high relaxivity MRI contrast agents.

Gold nanoparticles functionalised with stable, fast water exchanging Gd3+ chelates as high relaxivity contrast agents for MRI

“…The water exchange rate constant and the activation enthalpy for water exchange were fixed in the fittings to values (k ex 298 = 5.14x10 7 s -1 and ∆H ‡ = 17 J/mol) determined by us ) 16. As far as we are aware, there are no reports in the literature on the measurement of the exchange rate on Gd 3+ chelates immobilized on gold nanoparticles.…”

Complexes of Bifunctional DO3A-N-(α-amino)propinate Ligands with Mg(II), Ca(II), Cu(II), Zn(II), and Lanthanide(III) Ions: Thermodynamic Stability, Formation and Dissociation Kinetics, and Solution Dynamic NMR Studies

“…The Ln(DO3A-ACE) − and Ln(DO3A-BACE) − complexes have a single chiral center at their substituted acetate α-carbon, which is racemic as a consequence of the synthesis of the ligands [20,22]. The 1 H NMR spectrum of the paramagnetic Eu(DO3A-ACE) − complex in the solution corresponds to a dominant SA isomer conformation with C 1 symmetry, with a residual (2%) presence of the TSA isomer [20].…”

“…DO3A-ACE 4− and DO3A-BACE 4− were synthesized and purified according to procedures described in the literature [20,22]. Their purity was confirmed by 1 H, 13 C NMR as well as EA and ESI-MS analysis.…”

“…Obtaining optimal targeted GBCAs involves designing bifunctional chelators endowed with conjugability and leading to Gd 3+ chelates with high relaxivity, while maintaining high thermodynamic stability and kinetic inertness. We have recently reported the synthesis and in vitro and in vivo evaluation of Gd 3+ complexes of the DO3A-N-(αaminopropionate) chelator [20] and of some of its amide conjugates [21][22][23][24], (Scheme 1) as GBCAs for MRI, which have inspired other research groups [25]. The introduction of an amine group in the propionate pendant arm of DO3A-Nprop and its conjugation with various targeting model molecules did not affect the optimized k ex value, leading to high r 1 relaxivities at intermediate fields upon slowing down their tumbling rates via self-association or binding to gold nanoparticles, as well as efficient positive contrast in T 1 -weighted images of small animals [21][22][23][24].…”

“…We have recently reported the synthesis and in vitro and in vivo evaluation of Gd 3+ complexes of the DO3A-N-(αaminopropionate) chelator [20] and of some of its amide conjugates [21][22][23][24], (Scheme 1) as GBCAs for MRI, which have inspired other research groups [25]. The introduction of an amine group in the propionate pendant arm of DO3A-Nprop and its conjugation with various targeting model molecules did not affect the optimized k ex value, leading to high r 1 relaxivities at intermediate fields upon slowing down their tumbling rates via self-association or binding to gold nanoparticles, as well as efficient positive contrast in T 1 -weighted images of small animals [21][22][23][24]. Thus, in this work, we describe a detailed evaluation of the thermodynamic stability of the complexes of DO3A-N-(αaminopropionate) (DO3A-ACE 4− , H 4 DO3A-ACE = 1-(2-amino-carboxyethyl)-4,7,10-tris-(caboxymethyl)-1,4,7,10-tetraazacyclododecane) and of its benzoylamide conjugate (DO3A-BACE 4− , H 4 DO3A-BACE = 1-(2-benzylamido-carboxyethyl)-4,7,10-tris-(caboxymethyl)-1,4,7,10-tetraazacyclodode cane) (Scheme 1) with essential metal ions (Mg 2+ , Ca 2+ , Cu 2+ , and Zn 2+ ) and the lanthanide ions Ce 3+ , Gd 3+ , and Yb 3+ , as well as the formation kinetics of the Eu 3+ complexes and the dissociation kinetics of the Ce 3+ and Gd 3+ complexes, using pH-potentiometry, 1 H relaxometry, and UV-Vis spectrophotometry.…”