Gd (III) complexes are currently the most frequently used contrast agents to enhance cerebral pathologies using T_1w Magnetic Resonance Imaging. Clinically available Gd(III) chelates depict appropriate safety profiles, with very high stability constants difficulting transmetallation, and relatively fast renal elimination rates, decreasing systemic accumulation^1,2. These circumstances limit appropriately their potentially toxic repercussions and underlie their enormous clinical success. However, some Gd(III) chelates were shown to induce important toxicity responses as the nephrogenic systemic fibrosis (NSF) syndrome³, and a recent study showed that even healthy patients who received Gd(III) based contrast agents, presented Gd(III) accumulation in the brain, mainly in the globus pallidus and the dentate nucleus⁴. On these grounds we thought it would useful to characterize in more detail the pharmacokinetics of Gd(III)DTPA (Magnevist) in different brain structures after intravenous administration to healthy mice. We report here accurate measurements of the uptake, elimination and half-life of Magnevist (Gd(III) DTPA) in different regions of the healthy mouse brain. Our results show that the clearance of Magnevist varied widely in the brain regions analized, being faster in the cerebrospinal fluid of cerebral ventricles and subdural space and very much slower in the cortex, hypothalamus, globus pallidus and dentate nucleus.Animal protocols were approved by appropriate institutional committees. Adult C57BL6J male mice (30 g, n=6) were anesthetized with isofluorane/oxygen (2%) mixtures, their temperature maintained at 37⁰C during scanning with a recirculating water bath. T₁-weighted images of the mouse brain (MSME sequence, TE: 10.64ms, TR: 400ms, 3 Averages, 256x256, 14 slices) were successively acquired (3,84 min acquisition each) before (5 images) and after (80 images) Gd(III)DTPA injection (0,3M/100 mL) in the tail vein. Images were analyzed using Image J software, fitting intensity changes to a biexponential model $$$(I=a\cdot e^{-k_{absb}\cdot t}+b\cdot e^{-k_{el}\cdot t})$$$ with R software yielding rate constants of Magnevist absorption (k_abs) and the elimination (k_el) in seven manually selected regions of the brain, including: cortex, hypothalamus, lateral ventricles, third ventricle, subdural space, dentate nucleus and globus pallidus (Figure 1).

Figure 2 shows representative results of the biexponential fittings in the different regions investigated. The ventricles and subdural space depict a faster intensity loss, revealing a fast elimination of Magnevist. However, in the cortex, hypothalamus, dentate nucleus and globus pallidus, the elimination was remarkably slower, indicating a much longer residence time of Magnevist in those regions. Table 1 summarizes the absorption and elimination rate constants, mean half-life, and time to 99% signal loss in of these region.

Calculated k_abs showed the rapid absorption in the highly permeable ventricles and hypothalamus, slowing down significantly in cortex, subdural space, globus pallidus and dentante nucleus (Figure 2). The half-life and the time when the intensity has a value equal to 0.01% of the initial intensity value depicted rapid clearance from the ventricles and subdural space. However, clearing 99% of the agent (t_99%) required 617 h. in the cortex, 245 h in the globus pallidus and approximately 100h in hypothalamus and dentate nucleus, revealing very high residence time of Magnevist in those regions. Considering the injected dose is approximatelly, 10 mmol/g body weight, it is easy to infer that, even after 99% Gd(III)DTPA has been cleared, significant amounts of Magnevist remain trapped to different extents in cerebral tissues.

Our results show that, despite Magnevist is quickly cleared from cerebral ventricles and subdural space, we detect a long high half-life of Magnevist in cerebral regions as cortex, hypothalamus, globus pallidus and dentate nucleus. These results reveal that MRI detectable Magnevist concentrations remain trapped in specific brain regions long time after the MRI scan.