MR imaging probes: design and applications

Abstract

This perspective outlines strategies towards the development of MR imaging probes that our lab has explored over the last 15 years. Namely, we discuss methods to enhance the signal generating capacity of MR probes and how to achieve tissue specificity through protein targeting or probe activation within the tissue microenvironment.

Figure 1

Gadolinium and manganese complexes described and discussed in this perspective.

Figure 2

Fibrin-targeting probe EP-2104R and type I collagen targeting probe EP-3353. Charges omitted for clarity.

Figure 3

Panel A shows a maximum projection image of the head of a rat with an intracranial thrombus taken after injection of EP-2104R. The regions denoted “B” and “D” show the sites of the two dimensional images shown in panels B and D, respectively. Panel B shows a region of bright signal located in the internal carotid artery (ICA) and branching into the middle cerebral artery (MCA). Panel C shows a description of the vascular anatomy in the region of the brain represented in Panel B. Panel D shows cross sectional images of the common carotid arteries. The arrows denote mural thrombus along the vessel wall and of clotted side branches. The arrowhead shows the patent contralateral carotid artery. Adapted with permission from reference 60.

Figure 4

Top: Axial T₁-weighted image (4.7T) of liver in healthy control (Ishak 0, left) and severely fibrotic (Ishak 5, right) mice. False color scale depicts difference in liver to muscle contrast to noise (ΔCNR) ratio pre- and post-injection of EP-3353. Bottom Left: Correlation between ΔCNR and Ishak score. Bottom right: Correlation between ΔCNR and liver hydroxyproline concentration calculated ex vivo. Adapted with permission from reference 71.

Figure 5

Molecular parameters that influence inner- and 2nd-sphere relaxivity.

Figure 6

Libraries of HSA-binding Gd complexes. Complex type A was a library where R₁ and R₂ groups were varied to enhance second sphere relaxivity, while the D₁ donor group was varied to offset the slow water exchange effect of the two acetamide donors. Complex type B was a library that explored the effect of a single donor group D₁ variation on water exchange kinetics, electronic relaxation, and how these affected relaxivity. See also Figure 8.

Figure 7

Strategies to closely control rotational dynamics. a) Binding of two protein binding groups to one targeting molecule results in restriction of the rotation of two of the chelates (as indicated by small arrows) by dual attachment (indicated in blue). b) A multimer of the single amino acid Gd chelate Gd(DOTAla) also provides dual attachment of the Gd complex through the α carbon, as well as the carbonyl of the peptide backbone (indicated by asterisks). It is also important to note that in both cases, the chelators were attached using short linkers to ensure maximum rigidity.

Figure 8

a) Varied donor group D₁ from Figure 6, complex type B, resulting in q=1, HSA binding complexes with Gd. b) Relaxivity of these complexes in HSA solution at 37 °C plotted versus measured water residency time at 37 °C with data at 20 MHz (▴) and 60 MHz (▵). It is evident that τ_m limits relaxivity at a given field strength if it is either too long or too short, and that there is an optimal water exchange rate range for high relaxivity that becomes larger at higher fields. Reproduced with permission from reference 90.

Figure 9

For [Mn^IIHBET]^2−/1−, reversible switching between the Mn(II) and Mn(III) oxidation states can be achieved using glutathione (GSH) to increase relaxivity or H₂O₂ to decrease relaxivity. Adapted with permission from reference 155.

Figure 10

(A) PDI activation of mixed disulphide prodrug to fibrin binding EP-2104R. (B) In the presence of PDI (filled symbols) but not the absence (open symbols), the prodrug activated and can displace a fluorescent probe bound to the soluble fibrin fragment DD(E). (C) PDI activation of the prodrug is also monitored by the increase in relaxivity upon binding to DD(E); filled symbols show 1/T₁ in presence of PDI and open symbols show no change in T₁ in absence of PDI. (D) T₁-weighted images of pelleted fibrin at 1.4T. From left to right: fibrin alone, prodrug +PDI, prodrug −PDI, EP-2104R (positive fibrin binding control) +/−PDI, linear thioether (negative control) +/−PDI. Prodrug only shows binding to fibrin in presence of PDI. Adapted with permission from reference 157.