Evaluation of Gadopiclenol and P846, 2 High-Relaxivity Macrocyclic Magnetic Resonance Contrast Agents Without Protein Binding, in a Rodent Model of Hepatic Metastases

Fries, Peter; Maßmann, Alexander; Robert, Philippe; Corot, Claire; Laschke, Matthias W.; Schneider, Günther; Buecker, Arno; Müller, Andreas

doi:10.1097/rli.0000000000000572

Cited by 15 publications

(16 citation statements)

References 48 publications

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“…The r1-relaxivities (37°C, pH 7.4) of gadoquatrane were determined in human plasma at 1.41 T (per Gd: 11.8 mM −1 ·s −1 corresponding to 47.2 mM −1 ·s −1 per molecule) and 3.0 T (per Gd: 10.5 mM −1 s −1 corresponding to 41.9 mM −1 s −1 per molecule) (Table 1). The r1-relaxivity of gadoquatrane in human plasma was more than 2-fold (8-fold per molecule) higher compared with established GBCAs 22,23 …”

Section: Resultsmentioning

confidence: 86%

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Preclinical Profile of Gadoquatrane

Lohrke¹,

Berger

Frenzel³

et al. 2022

Invest Radiol

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Objectives The aim of this report was to characterize the key physicochemical, pharmacokinetic (PK), and magnetic resonance imaging (MRI) properties of gadoquatrane (BAY 1747846), a newly designed tetrameric, macrocyclic, extracellular gadolinium-based contrast agent (GBCA) with high relaxivity and stability. Materials and Methods The r1-relaxivities of the tetrameric gadoquatrane at 1.41 and 3.0 T were determined in human plasma and the nuclear magnetic relaxation dispersion profiles in water and plasma. The complex stability was analyzed in human serum over 21 days at pH 7.4 at 37°C and was compared with the linear GBCA gadodiamide and the macrocyclic GBCA (mGBCA) gadobutrol. In addition, zinc transmetallation assay was performed to investigate the kinetic inertness. Protein binding and the blood-to-plasma ratio were determined in vitro using rat and human plasma. The PK profile was evaluated in rats (up to 7 days postinjection). Magnetic resonance imaging properties were investigated using a glioblastoma (GS9L) rat model. Results The new chemical entity gadoquatrane is a macrocyclic tetrameric Gd complex with one inner sphere water molecule per Gd ( q = 1). Gadoquatrane showed high solubility in buffer (1.43 mol Gd/L, 10 mM Tris-HCl, pH 7.4), high hydrophilicity (logP −4.32 in 1-butanol/water), and negligible protein binding. The r1-relaxivity of gadoquatrane in human plasma per Gd of 11.8 mM −1 ·s −1 (corresponding to 47.2 mM −1 ·s −1 per molecule at 1.41 T at 37°C, pH 7.4) was more than 2-fold (8-fold per molecule) higher compared with established mGBCAs. Nuclear magnetic relaxation dispersion profiles confirmed the more than 2-fold higher r1-relaxivity in human plasma for the clinically relevant magnetic field strengths from 0.47 to 3.0 T. The complex stability of gadoquatrane at physiological conditions was very high. The observed Gd release after 21 days at 37°C in human serum was below the lower limit of quantification. Gadoquatrane showed no Gd 3+ release in the presence of zinc in the transmetallation assay. The PK profile (plasma elimination, biodistribution, recovery) was comparable to that of gadobutrol. In MRI, the quantitative evaluation of the tumor-to-brain contrast in the rat glioblastoma model showed significantly improved contrast enhancement using gadoquatrane compared with gadobutrol at the same Gd dose administered (0.1 mmol Gd/kg body weight). In comparison to gadoterate meglumine, similar contrast enhancement was reached with gadoquatrane with 75% less Gd dose. In terms of the molecule dose, this was reduced by 90% when compared with gadoterate meglumine. Because of its tetrameric structure and hence lower number of molecules per volume, all prepared formulations of gadoquatrane were iso-osmolar to blood. Conclusions The tetrameric...

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Section: Resultsmentioning

confidence: 86%

“…The r1-relaxivity of gadoquatrane in human plasma was more than 2-fold (8-fold per molecule) higher compared with established GBCAs. 22 , 23 …”

Section: Resultsmentioning

confidence: 99%

Preclinical Profile of Gadoquatrane

Lohrke¹,

Berger

Frenzel³

et al. 2022

Invest Radiol

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“…Gadopiclenol is a new high relaxivity macrocyclic GBCA. Preclinical studies have shown that this new macrocyclic chelate injected at the same dose as currently approved GBCAs improves the contrast-to-noise ratio in tumors by a factor of 2 to 3, as demonstrated in rat models of liver tumors 39 or brain gliomas 40 . Phase 3 clinical trials have just been completed.…”

Section: Discussionmentioning

confidence: 98%

Small Brain Lesion Enhancement and Gadolinium Deposition in the Rat Brain

Violas

Rasschaert²,

Santus³

et al. 2021

Invest Radiol

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Objectives: The aim of the set of studies was to compare gadopiclenol, a new high relaxivity gadolinium (Gd)-based contrast agent (GBCA) to gadobenate dimeglumine in terms of small brain lesion enhancement and Gd retention, including T1 enhancement in the cerebellum. Materials and Methods: In a first study, T1 enhancement at 0.1 mmol/kg body weight (bw) of gadopiclenol or gadobenate dimeglumine was evaluated in a small brain lesions rat model at 2.35 T. The 2 GBCAs were injected in an alternated and cross-over manner separated by an interval of 4.4 ± 1.0 hours (minimum, 3.5 hours; maximum, 6.1 hours; n = 6). In a second study, the passage of the GBCAs into cerebrospinal fluid (CSF) was evaluated by measuring the fourth ventricle T1 enhancement in healthy rats at 4.7 T over 23 minutes after a single intravenous (IV) injection of 1.2 mmol/kg bw of gadopiclenol or gadobenate dimeglumine (n = 6/group). In a third study, Gd retention at 1 month was evaluated in healthy rats who had received 20 IV injections of 1 of the 2 GBCAs (0.6 mmol/kg bw) or a similar volume of saline (n = 10/group) over 5 weeks. T1 enhancement of the deep cerebellar nuclei (DCN) was assessed by T1-weighted magnetic resonance imaging at 2.35 T, performed before the injection and thereafter once a week up to 1 month after the last injection. Elemental Gd levels in central nervous system structures, in muscle and in plasma were determined by inductively coupled plasma mass spectrometry (ICP-MS) 1 month after the last injection. Results: The first study in a small brain lesion rat model showed a ≈2-fold higher number of enhanced voxels in lesions with gadopiclenol compared with gadobenate dimeglumine. T1 enhancement of the fourth ventricle was observed in the first minutes after a single IV injection of gadopiclenol or gadobenate dimeglumine (study 2), resulting, in the case of gadopiclenol, in transient enhancement during the injection period of the repeated administrations study (study 3). In terms of Gd retention, T1 enhancement of the DCN was noted in the gadobenate dimeglumine group during the month after the injection period. No such enhancement of the DCN was observed in the gadopiclenol group. Gadolinium concentrations 1 month after the injection period in the gadopiclenol group were slightly increased in plasma and lower by a factor of 2 to 3 in the CNS structures and muscles, compared with gadobenate dimeglumine. Conclusions: In the small brain lesion rat model, gadopiclenol provides significantly higher enhancement of brain lesions compared with gadobentate dimeglumine at the same dose. After repeated IV injections, as expected for a macrocyclic GBCA, Gd retention is minimalized in the case of gadopiclenol compared with gadobenate dimeglumine, resulting in no T1 hypersignal in the DCN.

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“…It was shown some time ago that lanthanide complexes of the heptadentate ligand PCTA (3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid), which contain a pyridine moiety fused to the cyclen ring, have surprisingly high kinetic inertness for a bishydrated chelate [ 55 ]. Both of these principles (pyridine fusion and sidearm substitution) were applied in the design of Gadopiclenol, a high relaxivity GBCA currently in human clinical trials [ 56 , 57 , 58 , 59 ] to achieve excellent kinetic stability. A 2- to 3-fold greater relaxivity enhancements compared with current GBCA were achieved through a combination of two coordinating water molecules and slower molecular motion [ 57 ].…”

Section: What Structural Features Govern Kinetic Inertness?mentioning

confidence: 99%

How the Chemical Properties of GBCAs Influence Their Safety Profiles In Vivo

2021

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The extracellular class of gadolinium-based contrast agents (GBCAs) is an essential tool for clinical diagnosis and disease management. In order to better understand the issues associated with GBCA administration and gadolinium retention and deposition in the human brain, the chemical properties of GBCAs such as relative thermodynamic and kinetic stabilities and their likelihood of forming gadolinium deposits in vivo will be reviewed. The chemical form of gadolinium causing the hyperintensity is an open question. On the basis of estimates of total gadolinium concentration present, it is highly unlikely that the intact chelate is causing the T1 hyperintensities observed in the human brain. Although it is possible that there is a water-soluble form of gadolinium that has high relaxitvity present, our experience indicates that the insoluble gadolinium-based agents/salts could have high relaxivities on the surface of the solid due to higher water access. This review assesses the safety of GBCAs from a chemical point of view based on their thermodynamic and kinetic properties, discusses how these properties influence in vivo behavior, and highlights some clinical implications regarding the development of future imaging agents.

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Evaluation of Gadopiclenol and P846, 2 High-Relaxivity Macrocyclic Magnetic Resonance Contrast Agents Without Protein Binding, in a Rodent Model of Hepatic Metastases

Cited by 15 publications

References 48 publications

Preclinical Profile of Gadoquatrane

Preclinical Profile of Gadoquatrane

Small Brain Lesion Enhancement and Gadolinium Deposition in the Rat Brain

How the Chemical Properties of GBCAs Influence Their Safety Profiles In Vivo

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