Yttrium-86 PET imaging in rodents to better understand the biodistribution and clearance of gadolinium-based contrast agents used in MRI.

346 Objectives: Gadolinium-based contrast agents (GBCAs) have been used in combination with MRI for more than three decades1 and are considered extremely safe. However, trace amounts of gadolinium have been detected in the skin and central nervous system of patients with normal renal function, months to years after administration of a GBCA.2 The biodistribution and clearance of the commercially available GBCAs as well as the chemical form of the retained gadolinium species remain to be fully understood.3 Yttrium(III) and Gd(III) have very similar ionic radii leading to very similar chemical behavior. The objective of this work was to determine if Y-86 (t1/2 = 14.7h, 31.9% β+) could serve as a PET imaging reporter for Gd in GBCAs. Methods: Biodistribution study in mice. An equimolar solution of Y-DTPA and Gd-DTPA complexes at pH 7 was prepared and the absence of free Y3+ or Gd3+ was confirmed by HPLC coupled to ICP-MS. 6 mice were administered, by IV injection, a dose of Y/Gd-DTPA at 0.6 mmol/kg and sacrificed 7 days after injection. 21 organs and tissues were collected and digested in nitric acid with dysprosium used as an internal standard. Y and Gd concentration were measured by ICP-MS. 86Y Radiolabeling. DTPA was incubated with 86YCl3 in sodium citrate buffer at pH 6 at 80°C. After 15 minutes, the quantitative labeling was confirmed by radioHPLC using an HILIC column. The solution was purified on a chelex column and filtered through a 0.2 μm filter. PET/MR imaging and biodistribution in rats. 4 rats were administered, by IV injection, a microdose of 86Y-DTPA (135-157 μCi) mixed with a commercial solution of Gd-DTPA at 0.6 mmol/kg and scanned 7 to 11h and 52 to 56h after injection. After the last scan, rats were sacrificed, and the organs collected. The counts in each organ were measured using a Wizard gamma counter. The organs were then digested in nitric acid and the Gd concentration measured by ICP-MS. Results: 7 days after the concomitant injection of 0.6 mmol/kg Y-DTPA/Gd-DTPA in mice, the yttrium and gadolinium concentration per organ or tissues were very similar, Figure 1A, with no statistically significant differences and the Y:Gd ratio was close to 1 demonstrating very similar in vivo behavior of the two complexes, Figure 1B. The highest concentration was detected in the kidneys (Figure 1A). DTPA was quantitatively labeled with yttrium-86. PET-MR imaging of rats 56h after injection of 86Y-DTPA/Gd-DTPA demonstrated that the residual contrast agent in the kidneys could be detected by PET. ICP-MS of digested kidney revealed a similar concentration of Gd as predicted by the measurement of radioactivity. Conclusions: Y3+ can be used as a surrogate for Gd3+ in GBCAs. Yttrium-86 labeled GBCAs represents a useful new tool to study the whole body distribution and elimination of GBCAs over a 2 to 3 day period after administration. Research support. National Institute for Biomedical Imaging and Bioengineering for funding (EB009062). 1) J. Wahsner, E. M. Gale, A. Rodriguez-Rodriguez and P. Caravan, Chem. Rev., 2018, Article ASAP. 2) R. J. McDonald, D. Levine et al. Radiology, 2018, 289, 517-534. 3) M. Le Fur and P. Caravan, Metallomics, 2019, Advance Article. Figure 1: Biodistribution in mice. A) Amount of retained gadolinium and yttrium measured in the harvested organs and tissues, expressed in nmol of Gd per gram of wet tissue, 7 days after injection of a solution of Gd-DTPA and Y-DTPA at 0.6 mmol/kg. [asterisk]The amount of Gd and Y measured in the blood was below the limit of quantification. B) Y to Gd ratio in the harvested organs and tissues calculated from the Y and Gd concentrations (nmol/g) after injection of Y/Gd-DTPA. The red dashed lines correspond to the mean ratio. Figure 2: A) MR images of a rat 56h after injection of a mixture of 86Y-DTPA (153 μCi) and Magnevist (0.6 mmol/kg). B) PET images are superimposed to the MR images. The crosshairs show the position of the right kidney.