A Second Generation Mn-Porphyrin Dimer with a Twisted Linker as a Potential Blood Pool Agent for MRI: Tuning the Geometry and Binding with HSA

Blood-pool agents (BPAs) are MRI contrast agents (CAs) characterized by their long circulation in the vascular system to provide an extended time window for high-resolution MR angiography (MRA). Prolonged vascular retention, however, impedes the excretion of BPAs. Therefore, chemical strategy to regulate the balance between retention and clearance is important to reach optimal pharmacokinetics. We recently developed MnP2, the first Mn(III)-porphyrin (MnP) based BPA. MnP2 shows high T1 relaxivity (r1) and high affinity to human serum albumin (HSA) that leads to up to 48-h vascular retention in rats. However, upon albumin binding, the r1 is decreased. To modulate vascular retention time and plasma r1, a regioisomer of MnP2, m-MnP2, was synthesized. The free m-MnP2 exhibits lower r1 than that of MnP2 at magnetic fields above 2 MHz, which agrees with their relative hydrodynamic sizes. The HSA binding of m-MnP2 was evaluated using UV-Vis spectroscopy and found to have tuned-down affinity in comparison with MnP2. Upon HSA binding, the protein complex of m-MnP2 exhibits an r1 of 11.8 mM−1 s−1 at 3 T, which is higher than that of MnP2 bound to HSA. Taken together, this demonstrated the role of molecular geometry in optimizing the pharmacokinetics of albumin-targeting BPAs.

Biological effects of MRI contrast agents: gadolinium retention, potential mechanisms and a role for phosphorus

No discussion of challenges for chemistry in molecular imaging would be complete without addressing the elephant in the room—which is that the purest of chemical compounds needs to interact with a biological system in a manner that does not perturb normal biology while still providing efficacious feedback to assist in diagnosis of disease. In the past decade, magnetic resonance imaging (MRI) agents long considered inert have produced adverse effects in certain patient populations under certain treatment regimens. More recently, inert blood pool agents have been found to deposit in the brain. Release of free metal is often suspected as the culprit but that hypothesis has yet to be validated. In addition, even innocuous agents can cause painful side effects during injection in some patients. In this brief review, we summarize known biological effects for gadolinium- and iron-based MRI contrast agents, and discuss some of the potential mechanisms for the observed biological effects, including the potential role of phosphorus imbalance, related to kidney disease or cancer, in destabilizing gadolinium-based chelates and precipitating free gadolinium. This article is part of the themed issue ‘Challenges for chemistry in molecular imaging’.