Long-term Gadolinium Retention in the Healthy Rat Brain: Comparison between Gadopiclenol, Gadobutrol, and Gadodiamide

Background Safety concerns caused by gadolinium retention call for the development of high-relaxivity gadolinium-based contrast agents (GBCAs) allowing minimal dosing. Purpose To investigate brain gadolinium retention in healthy rats after exposure to gadopiclenol (Elucirem, Guerbet; macrocyclic GBCA) compared with gadobutrol (Gadovist or Gadavist, Bayer; macrocyclic GBCA) and gadodiamide (Omniscan, GE Healthcare; linear GBCA) over 1 year. Materials and Methods In this study conducted between May 2018 and April 2020, 9-week-old healthy Sprague Dawley rats received five injections of either gadopiclenol, gadobutrol, or gadodiamide (2.4 mmol of gadolinium per kilogram of body weight for each), or saline (control animals) over a period of 5 weeks. Rats were randomly assigned to different groups (six female and six male rats per group). MRI examinations were performed before euthanasia at 1, 3, 5, or 12 months after the last injection. Brains were sampled to determine the total gadolinium content via inductively coupled plasma mass spectrometry (ICP-MS), to characterize gadolinium species with size exclusion chromatography (SEC)-ICP-MS, and to perform elemental mapping with laser ablation (LA)-ICP-MS. Mann-Whitney tests were performed on pairwise comparisons of the same time points. Results For both macrocyclic agents, no T1 signal hyperintensities were observed in the cerebellum, and approximately 80% of gadolinium washout was found between 1 month (gadobutrol, 0.30 nmol/g; gadopiclenol, 0.37 nmol/g) and 12 months (gadobutrol, 0.062 nmol/g; gadopiclenol, 0.078 nmol/g). After 12 months, only low-molecular-weight gadolinium species were detected in the soluble fraction. Gadodiamide led to significantly higher gadolinium concentrations after 1 month in the cerebellum (gadodiamide, 2.65 nmol/g; P < .001 vs both macrocyclics) combined with only 15% washout after 12 months (gadodiamide, 2.25 nmol/g) and with gadolinium detected bound to macromolecules. Elemental bioimaging enabled visualization of gadolinium deposition patterns colocalized with iron. Conclusion Gadopiclenol and gadobutrol demonstrated similar in vivo distribution and washout of gadolinium in the healthy rat brain, markedly differing from gadodiamide up to 12 months after the last injection. © RSNA, 2022 Online supplemental material is available for this article.