Amplifying the Sensitivity of Zinc(II) Responsive MRI Contrast Agents by Altering Water Exchange Rates

Abstract

Given the known water exchange rate limitations of a previously reported Zn(II)-sensitive MRI contrast agent, GdDOTA-diBPEN, new structural targets were rationally designed to increase the rate of water exchange to improve MRI detection sensitivity. These new sensors exhibit fine-tuned water exchange properties and, depending on the individual structure, demonstrate significantly improved longitudinal relaxivities (r1). Two sensors in particular demonstrate optimized parameters and, therefore, show exceptionally high longitudinal relaxivities of about 50 mM−1 s−1 upon binding to Zn(II) and human serum albumin (HSA). This value demonstrates a 3-fold increase in r1 compared to that displayed by the original sensor, GdDOTA-diBPEN. In addition, this study provides important insights into the interplay between structural modifications, water exchange rate, and kinetic stability properties of the sensors. The new high relaxivity agents were used to successfully image Zn(II) release from the mouse pancreas in vivo during glucose stimulated insulin secretion.

Zinc-sensitive MRI contrast agent detects differential release of Zn(II) ions from the healthy vs. malignant mouse prostate

“…Gd-CP027 was prepared using published procedures by coupling two Zn(II) binding moieties to a 1,7-diprotected DO2A (28). Deprotection and complexation with Gd(III) afforded the target molecule, which was then subjected to extensive preparative HPLC purification.…”

“…Gd-CP027 exhibits a modest r 1 relaxivity of 5.6 ± 0.1 mM −1 ·s −1 in the absence of Zn(II) ions (Fig. 1A), but after formation of a ternary Gd-CP027-(Zn) 2 complex and subsequent binding to HSA, the r 1 relaxivity of the agent increases to 9.4 ± 0.2 mM (28). After injection of glucose and the agent, the mice were imaged sequentially over a period of ∼30 min or longer to follow contrast enhancement and washout of the agent from tissues (Fig.…”

A Janus Chelator Enables Biochemically Responsive MRI Contrast with Exceptional Dynamic Range

“…For Gd-based agents, the largest dynamic ranges reported are achieved via reactions that result in products that constrain Gd rotational dynamics. 11,12 Altering rotational dynamics provides a profound effect at field strengths ≤1.5 T, but is nearly obsolete by 3.0T. 32 Mn-JED maintains a 3.3 to 5.0-fold r 1 change at 4.7T and 11.7T.…”

Probes for monitoring regulated exocytosis

“…Since light penetration or scattering may become a limiting factor for optical imaging in live animals, novel concepts and strategies would be required. Some emerging approaches have yielded promising results for in vivo studies, including intravital microscopy or microendoscopy [18, 60, 61], in vivo ACEE-Tagging followed by postmortal analysis [20], and magnetic resonance imaging [45, 62]. Future exploration of these and other imaging technologies will offer exciting opportunities for investigating physiological regulation of stimulus-secretion coupling in vivo.…”