Abstract
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Introduction: Gadolinium (Gd)-based contrast agents (GBCAs) are routinely used in clinical MR examinations to provide diagnostic information. However, the accumulation of Gd in brain, bone, and skin of patients after receiving GBCAs and the direct link of GBCAs to the onset of nephrogenic systemic fibrosis (NSF), raised concerns about long-term health consequences. Manganese (Mn)-based contrast agents represent a potentially viable GBCA alternative. The Mn-based agent Mn-PyC3A was demonstrated to be chemically stable, with a relaxivity comparable to GBCAs [1-3]. In this study, we aim to quantify the pharmacokinetics, biodistribution, and elimination of Mn-PyC3A radiolabeled with Mn-52 in vivo in both normal rats and a rat model of end-stage renal failure (5/6 nephrectomy) using simultaneous PET/MRI, which enables us to distinguish low nmol/g quantities of retained exogenous Mn from basal tissue Mn.
Methods: Adult male and female Wistar rats and 5/6 nephrectomy (5/6 NX) rats were imaged at 4.7 T using a 40 cm-bore MR scanner with a PET insert of 20 cm in diameter with a FOV of 80 x 150 mm (Bruker Biospec). Animals were kept warm by blowing heated air. Temperature and respiration were monitored. Rats were imaged with MRI before contrast agent injection using a multislice 2-dimensional (2D) T1-weighted (T1w) fast low-angle low-shot (FLASH) sequence. An intravenous injection of 0.2 mmol/kg [52Mn]Mn-PyC3A (100-200 uCi) (Figure 1) formulated at 50 mM in sterile water was administered during the PET/MRI acquisition allowing for the biodistribution imaging of the PET tracer and the MRI contrast. Tissues were harvested at the end of the study and biodistribution of residual Mn quantified by gamma counting.
Results: Simultaneous PET/MR imaging in rats with nearly entire torso coverage was successfully achieved. Figure 2 shows the T1w FLASH MRI images before and 30 min after [52Mn]Mn-PyC3A injection showing strong signal enhancement in the kidneys, liver, and bile. Dynamic PET images at 1 min, 5 min, 30 min, 1 h, and 4 h post-injection PET images are shown in Figure 3 showing rapid blood clearance through a predominantly renal pathway but also some liver uptake and clearance into the bile. Time-activity curves for kidney, heart and liver in Figure 4 show renal and hepatic excretion pathways with rapid clearance within 1 hr. Together, the results are consistent with rapid elimination by a mixed renal and hepatobiliary path. Dechelated Mn is known to accumulate in the myocardium, pancreas, and certain glands, but little to no PET signal was detected in these organs over the entire study consistent with high in vivo stability and rapid elimination of Mn-PyC3A in both normal and 5/6 NX rats. Biodistribution analysis of 41 tissues at 24 h showed that 0.32±0.12 %ID and 2.0±1.1 %ID recovered from normal rats and 5/6 NX rats 1 day after injection, respectively, and 0.058±0.051 %ID and 0.14±0.11 %ID recovered from normal and 5/6 NX rats 7 days after injection. Quantities exceeding >0.05 %ID were recovered from the bone, cecum, colon, kidney, liver, skin, and stomach of 5/6NX rats 1 day after injection, but these values decreased to <0.05 %ID by 7 days for all groups analyzed (Figure 5). Conclusion: Dynamic and delayed phase PET/MR results confirm rapid renal and hepatobiliary clearance of Mn-PyC3A in both normal and 5/6 nephrectomized rats with nearly complete elimination within 24 h. This study demonstrates the utility of Mn-52 PET to characterize novel MRI contrast agents. Acknowledgements: Funding from the National Institutes of Health (R44DK113906, S10OD023503, K25HL128899, and R01DK120663) is gratefully acknowledged.
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