Nuclear microscopy: a novel technique for quantitative imaging of gadolinium distribution within tissue sections.

All clinically-approved and many novel gadolinium (Gd)-based contrast agents used to enhance signal intensity in magnetic resonance imaging (MRI) are optically-silent. To verify MRI results, a “gold standard” that can map and quantify Gd down to the parts per million (ppm) levels is required. Nuclear microscopy is a relatively new technique that has this capability, and is composed of a combination of the three ion beam techniques: scanning transmission ion microscopy (STIM), Rutherford back scattering spectrometry (RBS) and particle induced X-ray emission (PIXE) used in conjunction with a high energy proton microprobe. In this proof-of-concept study, we show that in diseased aortic vessel walls obtained at 2 hours and 4 hours after intravenous injection of the myeloperoxidase-senstitive MRI agent, bis-5-hydroxytryptamide-diethylenetriamine-pentaacetate gadolinium, there was a time-dependant Gd clearance (2-hr = 18.86 ppm, 4-hr = 8.65 ppm). As expected, the control animal, injected with the clinically-approved conventional agent diethylenetriamine-pentaacetate gadolinium and sacrificed 1 week after injection, revealed no significant residual Gd in the tissue. Similar to known in vivo Gd pharmacokinetics, we found that Gd concentration dropped by a factor of two in vessel wall tissue in 1.64 hrs. Further high-resolution studies revealed that Gd was relatively uniformly distributed, consistent with random agent diffusion. We conclude that nuclear microscopy is potentially very useful for validation studies involving Gd-based MR contrast agents.