A (Fluoroalkyl)Guanidine Modulates the Relaxivity of a Phosphonate-Containing T 1 -Shortening Contrast Agent

Abstract

Responsive magnetic resonance imaging (MRI) contrast agents, those that change their relaxivity according to environmental stimuli, have promise as next generation imaging probes in medicine. While several of these are known based on covalent modification of the contrast agents, fewer are known based on controlling non-covalent interactions. We demonstrate here accentuated relaxivity of a T1-shortening contrast agent, Gd-DOTP5− based on non-covalent, hydrogen bonding of Gd-DOTP5− with a novel fluorous amphiphile. By contrast to the phosphonate-containing Gd-DOTP5− system, the relaxivity of the analogous clinically approved contrast agent, Gd-DOTA− is unaffected by the same fluorous amphiphile under similar conditions. Mechanistic studies show that placing the fluorous amphiphile in proximity of the gadolinium center in Gd-DOTP5− caused an increase in τm (bound-water residence lifetime or the inverse of water exchange rate, τm = 1/kex) and an increase in τR (rotational correlation time), with τR being the factor driving enhanced relaxivity. Further, these effects were not observed when Gd-DOTA− was treated with the same fluorous amphiphile. Thus, Gd-DOTP5− and Gd-DOTA− respond to the fluorous amphiphile differently, presumably because the former binds to the amphiphile with higher affinity. (DOTP = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraphosphonic acid; DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid).

Nano assembly and encapsulation; a versatile platform for slowing the rotation of polyanionic Gd3+‐based MRI contrast agents

“…(6) The T 1 of these protons is then short, owing to their proximity to the paramagnetic Gd 3+ ion. Exchange of these protons across sites on polymers, chelates and whatever water molecules are present in the aggregate facilitate proton movement to the shell interior.…”

“…Inside the NAC the second 'hydration sphere' is probably replaced by protons from the PAH amino groups that hydrogen bond to the chelate, forming the aggregate (6). The T 1 of these protons is then short, owing to their proximity to the paramagnetic Gd 3+ ion.…”

“…These complications with Gd 3+ -based agents are the reason why many approaches to molecular imaging have focussed on the development of super paramagnetic nanoparticle-based contrast media (4)(5)(6)(7)(8). Although this type of contrast agent undoubtedly has the advantage of higher relaxivity and lower detection limits these gains come with drawbacks.…”

Aqueous Lanthanide Chemistry in Asymmetric Catalysis and Magnetic Resonance Imaging

“…27 Therefore, understanding the coordination chemistry of Gd III and other trivalent lanthanide ions is critical to the design of new contrast agents because the coordination of these ions impacts their ability to alter contrast and also changes their properties with respect to biodistribution and toxicity. We have explored trivalent ions as contrast agents, 28 but recently have focused a great deal of effort into divalent europium as a contrast agent.…”

Functionalized Gold Nanoparticles as Contrast Agents for Proton and Dual Proton/Fluorine MRI

“…However, fluorinated compounds can have relatively long relaxation times, resulting in long acquisition times [32]. This problem can be circumvented by introducing in the structure of the 19 F CA paramagnetic centers, such as Gd(III) in the proximity of 19 F nuclei, shortening T1 and allowing for the acquisition of a larger number of scans in the same experimental time [33,34,35,36]. In this context, Yu and coworkers reported that in a small, water soluble compound having nine equivalent fluorine atoms which is able to chelate gadolinium ions [37] the T1 shortening enabled by the paramagnetic center significantly improved the signal to noise ratio.…”