Experimental and Theoretical Study of Lanthanide Complexes Based on Linear and Macrocyclic Polyaminopolycarboxylic Acids with Pyrazolylethyl Arms

Elena Pérez-Mayoral,1 Elena Soriano,2 Sebastián Cerdán,2 and Paloma Ballesteros1 1Laboratorio de Síntesis Orgánica e Imagen Molecular por Resonancia Magnética, Instituto Universitario de Investigación, UNED, Facultad de Ciencias, UNED, Paseo Senda del Rey 9, E-28040 Madrid, Spain.2 Laboratorio de Resonancia Magnética, Instituto de Investigaciones Biomédicas, Arturo Duperier 4, E-28029 Madrid, Spain. E-mail: eperez@bec.uned.es


INTRODUCTION
Lanthanide complexation chemistry has acquired a large interest and rapid progress over the past several years.In particular, gadolinium We analyze the effect of including the 3,5-dimethylpyrazolylethyl moiety in the magnetic and complexation properties of the corresponding lanthanide complexes of 1 and 2, as compared with Gd (III)-dtpa and Gd(III)-dota.top
Basic hydrolysis of the obtained methyl aminoester yielded the compound 1 (scheme 1).Analogously, acidic hydrolysis of 4 gave the corresponding acetic acid which was characterized as its trisodium salt 2 (scheme 2).top

Relaxometric Study
Gd(III)-complexes have been synthesized using equimolecular amounts of the corresponding ligands and GdCl 3 •6H 2 O at room temperature for several minutes.They have been characterized by IR-FT (ATR) and ESI-MS (negative ions mode) finding 1:1 stoichiometry.
The efficacy of a potential contrast agent can be evaluated by its proton relaxivity (r 1 and r 2 ) in aqueous solutions expressed in s -1 mM -1 ECSOC-9 review copy (figure 1).Relaxivity was calculated from equation 1: Figure 1 shows r 1 and r 2 values of Gd-1 and Gd-2 as compared with Gd-dtpa and Gd-dota.Gd-1 exhibited a r 1(r2) maximum values, even higher than dtpa, while Gd-2 and dota presented similar relaxivity.
where, for every complexone, ∆ is the d rates (1 / T 1(2) ) of the water protons in p Gd(III)-complex, and [GdL] the molar con complex.The macrocyclic complex shown a stron thermodynamic stability and weak dissociation at acidic pH.

ECSOC-9 review copy
Considering the Solomon-Bloembergen-Morgan Theory, temperature dependence of r 1 is a qualitative assessment of the τ M , being r 1(2) , the longitudinal and transversal relaxivity, q, the hydration number (water molecules in the inner-sphere), T M the relaxation time of water protons of the water bound to metal center and finally, τ M the residence time of water in inner-sphere.It was observed an increased of water exchange rate in inner-sphere in Gd(III)-complexes of 1 and 2.
Hydration number, q, has been determined by 17 O NMR of the corresponding Dysprosium complexes (figure 4).
Then, hydration numbers (q) of the corresponding complexes have been determined from the slope of the concerned line as compared with the slope for DyCl 3 (q = 8) [6].For DyCl 3 , Gd-1 and Gd-2, the slope of the lines are 305.4(r 2 0.98), 62.7 (r 2 0.95) and 39.1 (r 2 0.98) ppm M -1 , repectively.Measurements of solutions of DyCl 3 •6H 2 O have been carried out at pH 3.5 while pH of the corresponding Dy-complexes solutions was around of 6.5-7.

Theoretical Calculations
Geometry optimizations were performed with Gaussian 98 [7] at the HF/3-21G/CPCM level with the ECP of Dolg et al. (46+4f 7 electrons in the core) [8].Then, single-point energy calculations were carried out at the density functional theory level (mPW1PW91 functional), using the 6-31+G** basis sets for the ligand.
The introduction of a pirazolethyl arm results in a shortening of the Gd-O and Gd-N distances for the acyclic system, and the methyl substituent induces steric compression around the water binding site, increasing the Gd-O W distance and favouring its departure [9].For the macrocyclic species, the metal center is displaced toward the plane formed by the carboxylate groups, giving rise to a longer Gd-N and shorter Gd-O and Gd-O W distances.While DOTA complex is slightly more stable than DTPA complex, Gd-2 appears as weakly less stable than Gd-1.The complexes bearing a pyrazolethyl ligand moiety are > 10 kcal/mol less stable than the model, for both acyclic and macrocyclic systems.*Relaxivity (r 1 and r 2 ) values of those are either higher or similar as compared with the parents compounds, Gd(III)-dtpa and Gd(III)-dota, respectively.

* Thermodynamic Stability
*The 3-methyl substituent on the pyrazolethyl arm induces a higher steric compression around the water binding site for dtpa-than for dota-derivatives, which can accelerate the water exchange process, thus increasing the relaxivity values.
*Activation energy results for the dissociation complex support the higher kinetic stability of the macrocyclic complexes.

(
III) complexes, derived of polyaminopolycarboxylic acids, are commonly used as contrast agents (CAs) in Magnetic Resonance Imaging (MRI) [1].The most commonly Gd-complexes used for this propose are [DTPA(Gd) 10-tetraacetic acids, respectively.More recently, several examples of chelating ligands including heterocyclic rings have been reported.Concretely, pyridine and tetrazole have been studied as isosteric groups of carboxylate moiety in polyaminopolycarboxylic acids[2].Here we describe the synthesis and relaxometric characterization of two novel chelating ligands 1 and 2 with 3,5-pyrazolylethyl arms (figure1).

Figure 2
Figure 2 and 3 despite the pH and temperature dependence of r 1 at 60 MHz, respectively. r

top
Activation energy (in kcal/mol) for the first step o dissociation process of the Gd-DTPA and Gd-D complexes.a Transition states in aqueous solution could not b characterized by vibrational analysis due t computational limitations.

Figure 6 .
Figure 6.Optimized transition structures for the first step of the dissociation process of the [Gd-L(H 2 O)] n-complexes.