In aqueous solutions, GdIII and thiacalix[4]arene-p-tetrasulfonate (TCAS) self-assembled to form a complex Gd3TCAS2, in which a GdIII3 core is sandwiched by two TCAS ligands as confirmed by EXAFS. Acid-catalyzed dissociation reaction yielded the solvolytic dissociation rate constant kd = (2.73 � 2.67) � 10�5 s�1 (25 �C), corresponding to a half-life of 7.1 h at pH 7.4. Furthermore, transmetallation with ZnII in the presence of phosphate confirmed the persistency under the physiological conditions; ca. 27% of the complex dissociated after 100 h. The high kinetic stability can be rationalized by the rigid coordination geometry supported by the sandwiched structure, which did not allow rearrangement of the coordination geometry of GdIII from the initial 8 coordinate to one suitable to 9 coordinate transition state. By comparison, Yb3TCAS2 showed much higher kinetic stability. The longitudinal relaxivity of Gd3TCAS2 (per GdIII) was r1 = 5.83 mM�1s�1 at 20 Hz (37 �C, pH 7.4), which was about 50% higher than conventional contrast agents such as Gd-DOTA and Gd-DTPA. Upon binding to human serum albumin (HSA), r1 did not increase, suggesting either an extremely slow water exchange rate (kex) or displacement of the water ligands upon binding to the protein. In fact, 17O NMR elucidated kex = (1.0 � 0.3) � 104 s�1 (25 �C), which is 1�4 orders of magnitude slower than common contrast agents. This slow water exchange rate is responsible for the low relaxivities observed in the presence and absence of HSA, despite the large number of coordinated water molecules to GdIII (q ~ 2). The slow water exchange rate of Gd3TCAS2 can be also attributed to the rigid coordination geometry to de-stabilize the transition state. Thus, the high kinetic stability and moderate relaxivity can be rationalized by the sandwich structure of Gd3TCAS2.

Can Gd3TCAS2 be a new motif of contrast agent for MRI? Unexpected slow water exchange arising from the tri-GdIII cluster sandwiched by two TCAS ligands (TCAS = thiacalix[4]arene-p-tetrasulfonate)

247th National Meeting (2014)

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