Next-Generation MRI Contrast Agents: Still Including Gadolinium

See also the article by Robert et al in this issue.

Download as PowerPointOpen in Image Viewer

Gadolinium-based contrast agents (GBCAs) have been used for 30 years to the great benefit of patients. Their overall safety has been exemplary, but concerns exist over long-term deposition of very small amounts of gadolinium that become dissociated from the active GBCA. Dissociated gadolinium can become deposited in various tissues, including central nervous system tissue, albeit in small quantities without known toxicity. These concerns have reignited research into new MRI contrast agents, with the aim of reducing or eliminating deposited gadolinium, especially in patients with renal impairment, pediatric patients, and patients likely to require multiple doses of contrast agents (1). Already there has been a great increase in the use of macrocyclic GBCAs that, as a class, have well-documented slower gadolinium-dissociation kinetics. Longer-term research is currently focused on substitution of GBCA with iron- or manganese-based agents and on creating GBCAs that can be used at lower doses (2–4).

In this issue of Radiology, Robert et al (5) report on the in vivo MRI signal-enhancing power of a new nonionic macrocyclic GBCA, gadopiclenol. Gadopiclenol contains a single gadolinium atom and has been engineered to produce two-to-three–fold greater T1 relaxivity than commercial agents without altering other fundamental physical characteristics (6,7). The authors use a well-known orthotopic rat brain glioma xenograft model (histologically confirmed; 24 rats, five to seven rats per group) to measure the dose dependence and kinetics of the MRI T1 signal evolution in tumor 0–30 minutes after administration. They report quantitative data as the contrast-to-noise ratio (CNR) between tumor and contralateral brain parenchyma. A fully blinded crossover experimental design was used to compare three commercial GBCAs (gadoterate meglumine, gadobutrol, and gadobenate dimeglumine) with gadopiclenol. The commercial GBCAs were administered at the human standard dose of 0.1 mmol per kilogram of body weight, and gadopiclenol was administered at doses of 0.025, 0.05, 0.075, 0.1, and 0.2 mmol/kg. Images were evaluated for precision in border delineation, quality of internal morphology depiction, and visual degree of contrast enhancement by using a scale from 1 (poor) to 4 (excellent).

A supplemental study was also performed in normal rats to compare cerebellar gadolinium deposition of gadopiclenol to that of gadobutrol and gadodiamide 5 months after repeat dosing (total dose, 12 mmol/kg). The level of gadolinium in the cerebellum with gadopiclenol was similar to that with macrocyclic gadobutrol. There was a very low retained amount of gadolinium compared with gadodiamide, a nonionic linear GBCA known for resulting in higher amounts of retained gadolinium.

There was linear improvement in ΔCNR as the dose of gadopiclenol increased between 0.025 and 0.1 mmol/kg. At 5 minutes after administration, the CNR of gadopiclenol at 0.05 mmol/kg was similar to that of the commercial agents at 0.1 mmol/kg. Comparing the agents at a dose of 0.1 mmol/kg, gadopiclenol produced statistically greater signal (ΔCNR = 12.9 ± 3.1 vs 5.3 ± 1.5 vs 7.1 ± 3.0, P ≤ .002). Qualitatively, gadopiclenol provided superior performance to the commercial agents at 0.05 and 0.1 mmol/kg in each evaluation category.

The greater relaxivity of gadopiclenol was engineered by combining three elements of GBCA design that have evolved over the past 30 years of research. GBCAs catalyze water-proton relaxation, which directly increases the T1 MRI signal. Water molecules bond very briefly to gadolinium to become relaxed. For gadopiclenol, chemists combined a modified and stiffened macrocyclic chelating agent with gadolinium to achieve a low gadolinium dissociation constant. But the molecular structure of gadopiclenol leaves enough open space to allow twice the number of water molecules as commercial GBCA to bind to the gadolinium atom. This increases relaxivity. A second innovation was also incorporated. When GBCAs are made to rotate more slowly in solution, the physics dictate an increase in relaxivity. Protein-binding agents like gadobenate and gadofosveset use this mechanism indirectly by transiently binding to large serum proteins. In gadopiclenol, the GBCA’s innate effective molecular volume was increased through bonded hydroxylated organic groups (6). The result is two-to-three–fold greater relaxivity.

Although gadopiclenol behaves similarly to commercial gadolinium agents in most respects, peak enhancement of gadopiclenol occurred 10–15 minutes after administration. Other GBCAs showed peak enhancement at 5 minutes. GBCAs enter brain tumors because of the lack of a mature blood-brain barrier otherwise found in normal brain that prevents GBCA entry. The chemical structure of gadopiclenol that increases relaxivity also results in a larger molecule with slower rotational and translational motion. The number and dimensions of abnormal endothelial fenestrae in brain tumors might be affecting the rate of gadopiclenol tumor pharmacokinetics because of its slightly larger volume or perhaps hydrogen bonding of the hydroxyl groups. If these characteristics cross over to human studies, gadopiclenol may have limited use for some tumors while providing a novel new tool to investigate tumor biology in others. Independent reports have shown that the pharmacokinetics and excretion of gadopiclenol are very similar to those of the commercial agents in humans. Human brain tumors are highly heterogeneous. It remains to be seen in which human tumors the gadopiclenol expresses its relaxivity advantage, to what degree, how soon after administration, and to what clinical advantages or disadvantages.

The study was imperfect, as the authors acknowledge. For example, the rat brain model is very highly vascularized compared with most human tumors. In addition, small rodent doses were not scaled by body mass to humans. Thus, the human standard dose, 0.1 mmol/kg, may be too low a dose to optimally predict behavior in humans.

I also caution the reader regarding the emphasis on comparing relaxivities and binding constants of gadolinium contrast agents. These physiochemical parameters are derived from in vitro data, but they are unreliable as surrogates for the more relevant in vivo data. For example, comparisons of thermodynamic binding constant “Keq” and “Kconditional” values correlate reasonably well with animal and human GBCA stability for the linear GBCAs. However, these in vitro physiochemical parameters show poor correlation with in vivo data for the macrocyclic GBCAs.

In summary, the study by Robert et al adds a well-developed initial proof-of-concept crossover study in a relevant animal model of primary brain tumors for a new GBCA. No doubt a similar clinical study is in the making, and the results will be eagerly awaited. Whether or not gadopiclenol is commercially successful, the significant technology evolution evidenced in gadopiclenol and the will to produce it are admirable. This level of technology advance takes years and costs tens of millions of dollars to produce. Gadopiclenol is the first really innovative GBCA for the central nervous system in decades.

Will the next generation of MRI agents include gadolinium? In my opinion, the answer appears to be “yes.” The use of gadolinium in MRI contrast agents is being challenged by iron- and manganese-based contrast agents, which have the obvious advantage of endogenous active metals (2,3). Iron and manganese contrast agents will need to overcome the inertia of vast and positive clinical experience with GBCAs. Is retaining half of the dissociated gadolinium by using gadopiclenol a significant advantage? If so, how significant? The toxicity of retained or deposited gadolinium remains unproven. Manganese- and iron-based agents guarantee zero retained gadolinium but are still administered as exogenous agents with unknown tolerance and with far less well-developed technologies than GBCAs. As these and many other details are sorted out, we appear to be headed into an exciting period of technology evolution in the field of MRI contrast agents.