Maximizing T₂-exchange in Dy³⁺DOTA-(amide) _X chelates: Fine-tuning the water molecule exchange rate for enhanced T₂ contrast in MRI

Purpose The water molecule exchange rates in a series of DyDOTA-(amide)_X chelates were fine-tuned to maximize the effects of T₂-exchange line broadening and improve T₂ contrast. Methods Four DyDOTA-(amide)_X chelates having a variable number of glycinate side-arms were prepared and characterized as T₂-exchange agents. The nonexchanging DyTETA chelate was also used to measure the bulk water T₂ reduction due solely to T₂*. The total transverse relaxivity (r_2tot) at 22, 37, and 52°C for each chelate was measured in vitro at 9.4 Tesla (400 MHz) by fitting plots of total T₂^-1 versus concentration. The water molecule exchange rates for each complex were measured by fitting ¹⁷O line-width versus temperature data taken at 9.4 Tesla (54.3 MHz). Results The measured transverse relaxivities due to water molecule exchange (r_2ex) and bound water lifetimes (τ_M) were in excellent agreement with Swift-Connick theory, with DyDOTA-(gly)₃ giving the largest r_2ex = 11.8 s^-1 mM^-1 at 37°C. Conclusion By fine-tuning the water molecule exchange rate at 37°C, the transverse relaxivity has been increased by 2 to 30 times compared with previously studied Dy³⁺-based chelates. Polymerization or dendrimerization of the optimal chelate could yield a highly sensitive, molecule-sized T₂ contrast agent for improved molecular imaging applications.