Towards extracellular Ca2+ sensing by MRI: synthesis and calcium-dependent 1H and 17O relaxation studies of two novel bismacrocyclic Gd3+ complexes

Abstract

Two new bismacrocyclic Gd 3+ chelates containing a specific Ca 2+ binding site were synthesized as potential MRI contrast agents for the detection of Ca 2+ concentration changes at the millimolar level in the extracellular space. In the ligands, the Ca 2+ -sensitive BAPTA-bisamide central part is separated from the DO3A macrocycles either by an ethylene (L 1 ) or by a propylene (L 2 ) unit [H 4 BAPTA is 1,2-bis(o-aminophenoxy)ethane-N,N,N 0 ,N 0 -tetraacetic acid; H 3 DO 3 A is 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid]. The sensitivity of the Gd 3+ complexes towards Ca 2+ and Mg 2+ was studied by 1 H relaxometric titrations. A maximum relaxivity increase of 15 and 10% was observed upon Ca 2+ binding to Gd 2 L 1 and Gd 2 L 2 , respectively, with a distinct selectivity of Gd 2 L 1 towards Ca 2+ compared with Mg 2+ . For Ca 2+ binding, association constants of log K = 1.9 (Gd 2 L 1 ) and log K = 2.7 (Gd 2 L 2 ) were determined by relaxometry. Luminescence lifetime measurements and UV-vis spectrophotometry on the corresponding Eu 3+ analogues proved that the complexes exist in the form of monohydrated and nonhydrated species; Ca 2+ binding in the central part of the ligand induces the formation of the monohydrated state. The increasing hydration number accounts for the relaxivity increase observed on Ca 2+ addition. A 1 H nuclear magnetic relaxation dispersion and 17 O NMR study on Gd 2 L 1 in the absence and in the presence of Ca 2+ was performed to assess the microscopic parameters influencing relaxivity. On Ca 2+ binding, the water exchange is slightly accelerated, which is likely related to the increased steric demand of the central part leading to a destabilization of the Ln-water binding interaction.

In Vivo Characterization of a Smart MRI Agent That Displays an Inverse Response to Calcium Concentration

“…Typically a modulation of the hydration number, q, is responsible for the changes in r 1 (9,10). Another class of responsive CAs (T 2 ) rely on a different mechanism, where the Ca 2þ -induced aggregation of DOI: 10.1021/cn100083a |ACS Chem.…”

Gadolinium Complexes of Bifunctional Diethylenetriaminepentaacetic Acid (DTPA)-bis(amides) as Copper Responsive Smart Magnetic Resonance Imaging Contrast Agents (MRI CAs)

“…19 The pM value reflects the influence of ligand basicity and protonation of the complex. 20 Thus, the larger the pM value, the higher the affinity of the ligand for the metal ion under the given conditions. Table 2 shows that higher pM values are achieved with Gd(III) than with Ca(II), Zn(II), or Cu(II): Indication is that complexes 2a-b are stable enough to avoid any interference by other endogenous metal ions.…”

“…In this regard, it is worth noting the recent advent of a variety of so-called 'targeting MRI CAs' capable of responding to particular organ(s), [3][4][5][6][7][8][9][10][11][12] pathologies (i.e., tumors, angiogenesis, apoptosis), [13][14][15][16] or biological stimuli (i.e., pH, 17 metal ions, [18][19][20][21][22][23][24][25][26][27][28][29] enzymes, 30-40 glucose 41,42 ). As part of our continued search for targeting MRI probes, we have recently reported a new bimodal magnetic resonance/single-photo emission computed tomography (MR/ SPECT) imaging probe based on the multi-nucleating chelates (1a-b) such as shown in Scheme 1.…”

Metal Complexes as MRI Contrast Enhancement Agents

“…A series of dimeric complexes have been reported for extracellular Ca 2+ sensing. 283,284 In one example, bisamide derivatives of EGTA have substituted the BAPTA in order to achieve Ca 2+ affinity in the millimolar range. 285 These compounds show a maximum Scheme 22 Two main strategies to modulate relaxivity through metal ion sensing.…”