Gadobenate

Gd-BOPTA

Cheng KT.

Publication Details

Image

Table

In vitro Rodents

Background

[PubMed]

Gadobenate (Gd-BOPTA) is a paramagnetic contrast agent for magnetic resonance imaging (MRI) that was approved by the United States Food and Drug Administration (US FDA) in 2004 for imaging the central nervous system to visualize lesions with abnormal blood-brain barrier (BBB) or abnormal vascularity of the brain, spine, and associated tissues (1-3).

Conventional, water-soluble, paramagnetic contrast agents are generally metal chelates with unpaired electrons, and they work by shortening both T1 and T2 relaxation times of surrounding water protons to produce the contrast-enhancing effect (1, 2). At normal clinical doses, the T1 effect tends to dominate. Current agents are water-soluble compounds that distribute in the extracellular fluid and do not cross the intact BBB. They can be used to enhance signals of CNS tissues that lack a BBB (e.g., pituitary gland), extraaxial tumors (e.g., meningiomas), and areas of BBB breakdown (e.g., tumor margins). In these cases, small or multiple CNS lesions are more clearly delineated with contrast enhancement. In addition, contrast enhancement can highlight vasculature, delineate the extent of disease, and confirm the impression of normal or nonmalignant tissues. These contrast agents can also be used in a similar nonspecific manner to enhance contrast between perfused and nonperfused areas in other organs (1, 2, 4).

Gadolinium ion (Gd3+), a lanthanide metal ion with seven unpaired electrons, has been shown to be very effective at enhancing proton relaxation because of its high magnetic moment and very labile water coordination (2, 5-7). Gadopentetate dimeglumine (Gd-DTPA) was the first intravenous MRI contrast agent used clinically, and a number of similar gadolinium chelates have been developed in an effort to further improve clinical efficacy, patient safety and patient tolerance. The major chemical differences among these Gd chelates or Gd-based contrast agents (GBCAs) are the presence or absence of overall charge, ionic or nonionic, and their ligand frameworks (linear or macrocyclic). Gd-BOPTA has a linear framework and is ionic. The BOPTA ligand was originally developed as a potential hepatobiliary agent for MRI (8). It is a modification of the DTPA molecule based on the belief that the addition of a benzoylmethyl group to the backbone of DTPA would increase the liver uptake of Gd-BOPTA. The hepatobiliary excretion of Gd-BOPTA appears to be species dependent, and only 2-5% of the dose is excreted via the biliary system in humans. Because of weak/transient interactions between Gd-BOPTA and macromolecules that reduce the tumbling rate of the Gd-BOPTA molecules, Gd-BOPTA demonstrates increased r1 and r2 relaxivities (efficiencies in shorteningT1 and T2 relaxation times) in solutions containing serum proteins (9-11).

The commercial formulation of Gd-BOPTA is a meglumine salt (Gd-BOPTA/Dimeg) and is available as a 0.5 M injection with a recommended dose of 0.1 mmol/kg (0.2 ml/kg) either as a rapid intravenous infusion or bolus injection for CNS MRI imaging (3, 12). It has an osmolality of 1970 osmol/kg and viscosity of 5.3 mPas at 37oC.

Both renal and extra-renal toxicities have been reported following the clinical use of gadolinium in patients with underlying kidney disease (13-15). In 2007, the US FDA requested manufacturers of all GBCAs to add new warnings about exposure to GBCAs increases the risk for nephrogenic systemic fibrosis (NSF) in patients with advanced kidney disease.

Synthesis

[PubMed]

Felder et al. (16) first synthesized the BOPTA ligand in 1987. Uggeri et al. (17) reported that the synthesis of BOPTA consisted of two major steps. Diethylenetriamine was first selectively monoalkylated on a primary amino group with 2-chloro-3-(phenylmethoxy)propanoic acid in water at 50oC for 40 h. The intermediate product was isolated as N-[2-[(2-aminoethyl)amino]ethyl]-O-(phenylmethyl)-dl-serine tris-(hydrochloride) with the yield of 58%. This intermediate compound was then fully carboxymethylated with bromoacetic acid in water at pH 10 and room temperature for 15 h, and the yield of BOPTA was 21%. Gd-BOPTA dimeglumine salt was prepared by mixing BOPTA with N-methylglucamine and Gd2O3 at 80oC for 1.5 h.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

In in vitro studies, Gd-BOPTA/Dimeg at a concentration of 30 mM caused a slight reduction of the contractile force in a rat papillary muscle preparation, and a mild decrease of both amplitude and contraction rate in isolated guinea pig atria (18).

The water proton relaxation of Gd-BOPTA in a protein-free aqueous solution was measured at 20 MHz, 39oC and pH 7.4, and its longitudinal (r1) and transverse (r2) relaxivities values in mM−1s−1were reported to be 4.39 ± 0.01 and 5.56 ± 0.02, respectively (11, 17). The conditional stability constant (log K*ml) of Gd-BOPTA determined by competition complexation experiments was 18.4 at pH 7.4 and 20oC. The r1 relaxivity of Gd-BOPTA in heparinzed human plasma was reported to be 9.7 mM−1s−1. Cavagna et al. (19) reported that no binding of Gd-DOPTA/Dimeg to serum proteins could be detected using equilibrium dialysis (detection sensitivity at equilibrium constants = or < 5 mM) against rat, rabbit, or human plasma. With the use of different bovine serum albumin (BSA) concentrations, an in vitro nuclear magnetic relaxation dispersion (NMRD) profile of Gd-BOPTA/Dimeg was constructed to show that protein concentrations had a strong influence on Gd-BOPTA/Dimeg relaxivity (20).

Caravan et al. (21) in a 2003 study found that the ion-nuclear distance of Gd to a coordinated water proton, rGd-H, was 3.1 ± 0.1 Å for Gd-BOPTA and four other Gd complexes. Partition coefficients of Gd-BOPTA/Dimeg in the systems of n-butanol or n-octanol with 0.01 M phosphate buffer pH 7.3 were found to be 0.0067 and 0.0016, respectively (22).

Planchamp et al. (23) used a hollow-fiber bioreactor to study the transport of Gd-BOPTA/Dimeg into rat hepatocytes. They reported that the results supported a transporter-mediated mechanism, and the Michaelis-Menton constant (Km) was estimated to be 270 µM. In another isolated rat liver study, the uptake of Gd-BOPTA into hepatocytes and its subsequent biliary excretion appeared to be highly temperature dependent (24).

Animal Studies

Rodents

[PubMed]

In rats, Gd-BOPTA/Dimeg rapidly distributed in the extravascular and extracellular compartments, and it showed a marked affinity for biliary excretion (19, 25). The biodistribution study showed that Gd-BOPTA/Dimeg was found mainly in the liver and kidney. Vittadini et al. (26) conducted pharmacokinetic studies of Gd-BOPTA/Dimeg (0.05 mmol/kg) in rats and found that the blood kinetics (distribution t½, elimination t½ and apparent volume of distribution Vd) and excretion kinetics of 6 h (total clearance, urinary excretion and biliary excretion) were 3.8 ± 0.5 min, 15.05 ± 0.54 min, 165.1 ml/kg and 13.9 ml/min/kg, 54.8 ± 8.8% injected dose (ID), 38.6 ± 7.3% ID, respectively. Cavagna et al. (19) reported that the bile and urine eliminations of Gd-BOPTA in rats at 8 h were 52% ID and 46% ID, respectively. There was no or weak binding of Gd-BOPTA/Dimeg to plasma proteins and no apparent biotransformation of the compound.

The acute i.v. LD50 of Gd-BOPTA/Dimeg in rats was 6.6 (5.8-7.5, n = 5) mmol/kg at 6 ml/min and 9.2 (8.1-10.4) mmol/kg at 0.2 ml/min (27). No observed effect levels (NOEL) were observed in rats with repeated doses up to 0.3 mmol/kg/day. Only a mild and transient reduction in heart rate was observed at the dose of 1 mmol/kg (18). Luzzani et al (28). studied the brain penetration and neurological effects of Gd-BOPTA in rats with various i.v. and intracisternal injection doses of 153Gd-BOPTA. At 0.01 mmol/kg of intracisternal injection of 153Gd-BOPTA/Dimeg, the motor coordination was slightly impaired. No neurological effect was observed with i.v. doses of 153Gd-BOPTA up to 2 mmol/kg. Noce et al. (29)did not find any effect of Gd-BOPTA on cerebral glucose metabolism after an intracerebral dose of 120 nmol/rat. In the same study, no genotoxic potential was observed in mutagenicity tests, and the reproductive performance and development of offspring were not affected at doses up to 20 times the human dose.

The acute i.v. LD50 of Gd-BOPTA/Dimeg in mice was 5.7 (5.3-6.2, n = 5) mmol/kg at 6 ml/min and 7.9 (7.5-8.3) mmol/kg at 0.2 ml/min (27). The intracerebral LD50 was 1.02 mmol/kg (26). In another preclinical study in rats, Gd-BOPTA/Dimeg at the i.v. dose of 1 mmol/kg caused a decrease of blood pressure of about 15%, a decrease of heart rate of about 7%, but no significant ECG alterations (22).

With the use of MRI imaging (2 Tesla, T1-weighted), in vivo relaxivity (r1) values of Gd-BOPTA/Dimeg (200 µmol/kg) in the blood, normal and infracted myocardium of rats were determined to be 6.19, 4.05, and 10.03 mM−1s−1, respectively (20). In comparison, the corresponding values for Gd-DTPA were reported to be 3.41, 3.52, and 5.32 mM−1s−1.

Pastor et al. (30) studied the hepatic kinetics of Gd-BOPTA/Dimeg with the use of MRI (1.5 Tesla, T1-weighted) in a perfused rat liver model. They found that the hepatic activity uptake t½ was 4.8 ± 0.3 min, and the washout t½ was 17.5 ± 2.8 min.

Other Non-Primate Mammals

[PubMed]

Lorusso and colleagues showed that Gd-BOPTA/Dimeg distributes into plasma, extracellular fluid, and intrahepatocytic space in both rabbits and dogs (25). Gd-BOPTA was not metabolized and was cleared from plasma by renal and biliary excretion.

Morisetti et al. (27) found no adverse effects of Gd-BOPTA/Dimeg treatment on rabbit dams or on fetuses at a dose of 0.3 mmol/kg per day. Cavagna et al. (19) used MRI (2 Telsa, T1-weighted) to perform the in vivo determination of the relaxation rate of Gd-BOPTA/Dimeg (0.1 mmol/kg) in rabbit blood. The longitudinal relaxation rate was 1.93 ± 0.06 s−1 at 5 min after injection.

No significant cardiovascular and respiratory effects of Gd-BOPTA/Dimeg at i.v. dose of 1 mmol/kg (10 ml/min) in Large White pigs (18). In a myocardial ischemia Yucatan micropig model, i.v. doses of Gd-BOPTA/Dimeg up to 3 mmol/kg did cause dose-dependent cardiovascular changes.

Port and colleagues (31) used a rabbit experimental model to determine that the dynamic relaxivity (r1dynamic) of Gd-BOPTA in plasma was 5.2 mM−1s−1 (60 MHz) at the bolus phase (0-15 sec postinjection) when 93% of Gd-BOPTA was present in the free form. The r1dynamic was 6.7 mM−1s−1 at the postbolus phase (1-5 min postinjection) when 82% of Gd-BOPTA remained in the free form.

Non-Human Primates

[PubMed]

The NOEL dose of Gd-BOPTA/Dimeg was found to be 0.25 mmol/kg/day (i.v.) in Cynomolgus monkeys (27) In the doses ranging from 0.25 to 3 mmol/kg, the maximal plasma concentration and the area under the plasma concentration-time curve were linearly related to the dose (25). Runge (32) studied MRI (1.5 Tesla, T1-weighted) of Gd-BOPTA/Dimeg at the dose of 0.1 mmol/kg in rhesus monkeys (n = 4). The enhancements (percent increase in signal intensity before injection) of the muscle, kidneys, and spleen were maximum at 2 min (40 ± 17%), 5 min (164 ± 25%), and 5 min (92 ± 25%) after injection, respectively. Two peaks of liver enhancement were observed with 114 ± 45% occurred immediately and then with 136 ± 23% occurred at 30 min after injection.

Human Studies

[PubMed]

The Phase I study by Spinazzi et al. (33) and the Phase II clinical trial by Rosati et al (34). reported the safety and pharmacokinetics data of Gd-BOPTA/dimeg. The pharmacokinetics profile was studied in 28 healthy volunteers. Gd-BOPTA/Dimeg was given in seven different i.v. doses ranging from 0.05 mmol/kg to 0.4 mmol/kg. In the dose range from 0.005 mmol/kg to 0.2 mmol/kg, the pharmacokinetics value ranges (n = 4) of the distribution t½, elimination t½, Vd, and the total clearance (CL) were 0.084-0.36 h, 1.17-1.68 h, 0.074-0.142 liter/kg, 0.170-0.248 liter/kg, and 0.098-0.133 liter/h/kg, respectively. In the dose range from 0.2 mmol/kg to 0.4 mmol/kg, the value ranges (n = 4 ) of the distribution t½, elimination t½, Vd, and CL were 0.48-0.605 h, 1.95-2.02 h, 0.147-0.158 liter/kg, 0.261-0.282 liter/kg, and 0.093-0.098 l/h/kg, respectively. In 72 h, 89-95.2% of the injected dose was eliminated unchanged by the kidneys and about 0.6-3.5% was excreted in the bile. With the use of equilibrium dialysis, the complex did not appear to bind measurably to plasma proteins. Safety studies in 39 volunteers indicated an18% of adverse events as compared with 14% in the placebo group (n = 14). The most frequent adverse events were altered sensation at the injection site, nausea, and sweating. In 127 patients with intracranial lesions, Gd-BOPTA/Dimeg (0.1-0.2 mmol/kg) provided better diagnostic information in 95% of the cases than those of MRI without contrast.

Phase III double-blind, multicenters (28 centers), randomized, parallel group comparative studies with 410 CNS patients had shown that Gd-BOPTA/Dimeg at doses of 0.05-0.15 mmol/kg and 0.1-0.2 mmol/kg had comparable safety and efficacy profiles as Gd-DTPA-BMA at doses of 0.1 mmol/kg and 0.3 mmol/kg for imaging of CNS lesions (35, 36). Other studies had investigated the potential usefulness of Gd-BOPTA/Dimeg for liver imaging [PubMed] and magnetic resonance angiography [PubMed].

References

1.
Brasch RC, Ogan MD, Engelstad BL. Paramagnetic Contrast Agents and Their Application in NMR Imaging, in Contrast media; Biologic effects and clinical application, Z. Parvez, R., R. Monada and M. Sovak, Editor. 1987, CRC Press, Inc.: Boca Raton, Florida. p. 131-143.
2.
Saini S, Ferrucci JT. Enhanced Agents for Magnetic Resonance Imaging: Clinical Applications, in Pharmaceuticals in Medical Imaging, D.P. Swanson, H.M. Chilton and J.H. Thrall, Editor. 1990, MacMillan Publishing Co., Inc.: New York. p. 662-681.
3.
multihance (gadobenate dimeglumine injection, 529 mg/ml) Package Insert. 2005: Bracco Diagnostics Inc. F1/3.541037.
4.
Runge V. , Kirsch J. , Wells J. , Awh M. , Bittner D. , Woolfolk C. Enhanced liver MR: Contrast agents and imaging strategy. Crit Rev Diagn Imaging. 1993; 34 (2):1–3. [PubMed: 8216813]
5.
DeSimone D. , Morris M. , Rhoda C. , Lucas T. , Zielonka J. , Olukotun A. , Carvlin M. Evaluation of the safety and efficacy of gadoteridol injection (a low osmolal magnetic resonance contrast agent). Clinical trials report. Invest Radiol. 1991; 26 :S212–S216. [PubMed: 1808133]
6.
Tweedle M. Physicochemical properties of gadoteridol and other magnetic resonance contrast agents. Invest Radiol. 1992; 27 :S2–S6. [PubMed: 1506149]
7.
Yuh W. , Engelken J. , Muhonen M. , Mayr N. , Fisher D. , Ehrhardt J. Experience with high-dose gadolinium MR imaging in the evaluation of brain metastases. AJNR Am J Neuroradiol. 1992; 13 (1):335–345. [PMC free article: PMC8331800] [PubMed: 1595472]
8.
Oksendal A. , Hals P. Biodistribution and toxicity of MR imaging contrast media. J Magn Reson Imaging. 1993; 3 (1):157–165. [PubMed: 8428083]
9.
Kirchin M. , Pirovano G. , Spinazzi A. Gadobenate dimeglumine (Gd-BOPTA). An overview. Invest Radiol. 1998; 33 (11):798–809. [PubMed: 9818314]
10.
Essig M. Gadobenate dimeglumine (MultiHance) in MR imaging of the CNS: studies to assess the benefits of a high relaxivity contrast agent. Acad Radiol. 2005; 12 :S23–S27. [PubMed: 16106542]
11.
de Haen C. , Cabrini M. , Akhnana L. , Ratti D. , Calabi L. , Gozzini L. Gadobenate dimeglumine 0.5 M solution for injection (MultiHance) pharmaceutical formulation and physicochemical properties of a new magnetic resonance imaging contrast medium. J Comput Assist Tomogr. 1999; 23 :S161–S168. [PubMed: 10608412]
12.
de Haen C. , Gozzini L. Soluble-type hepatobiliary contrast agents for MR imaging. J Magn Reson Imaging. 1993; 3 (1):179–186. [PubMed: 8428085]
13.
Perazella M.A. , Rodby R.A. Gadolinium use in patients with kidney disease: a cause for concern. Semin Dial. 2007; 20 (3):179–85. [PubMed: 17555477]
14.
Grobner T. , Prischl F.C. and Gadolinium and nephrogenic systemic fibrosis. Kidney Int. 2007 [PubMed: 17507905]
15.
Pedersen M. Safety update on the possible causal relationship between gadolinium-containing MRI agents and nephrogenic systemic fibrosis. J Magn Reson Imaging. 2007; 25 (5):881–3. [PubMed: 17457808]
  • 16. Felder, E., R. Vitale, F. Uggeri, L. Fumagalli, and G. Vittadini, 1990.
    • 17.
    Uggeri F. , Aime S. , Anelli P. , Botta M. , Brocchetta M. , de Haen C. , Ermondi G. , Grandi M. , Paoli P. Novel contrast agents for magnetic resonance imaging. Synthesis and characterization of the ligand BOPTA and its Ln(III) complexes (Ln=Gd, La, Lu). X-ray structure of disodium (TPS-9-145337286-C-S)-[4-carboxy-5,8,11-tris(carboxymethyl)-1-phenyl-2-oxa-5,8,11-triazatridecan-13-oato(5-)]gadolinate(2-) in a mixture with its enantiomer. Inorg Chem. 1995; 34 :633–642.
    18.
    Tirone P. , Castano M. , Cipolla P. , Frigeni V. , La Noce A. , Luzzani F. , Valenti R. , de Haen C. General pharmacology in experimental animals of gadobenate dimeglumine (MultiHance), a new magnetic resonance imaging contrast agent. J Comput Assist Tomogr. 1999; 23 :S195–S206. [PubMed: 10608415]
    19.
    Cavagna F. , Maggioni F. , Castelli P. , Dapra M. , Imperatori L. , Lorusso V. , Jenkins B. Gadolinium chelates with weak binding to serum proteins. A new class of high-efficiency, general purpose contrast agents for magnetic resonance imaging. Invest Radiol. 1997; 32 (12):780–796. [PubMed: 9406019]
    20.
    Cavagna F. , Marzola P. , Dapra M. , Maggioni F. , Vicinanza E. , Castelli P. , de Haen C. , Luchinat C. , Wendland M. , Saeed M. , Higgins C. Binding of gadobenate dimeglumine to proteins extravasated into interstitial space enhances conspicuity of reperfused infarcts. Invest Radiol. 1994; 29 :S50–S53. [PubMed: 7928270]
    21.
    Caravan P. , Astashkin A. , Raitsimring A. The gadolinium(III)-water hydrogen distance in MRI contrast agents. Inorg Chem. 2003; 42 (13):3972–3974. [PubMed: 12817950]
    22.
    Vittadini G. , Felder E. , Musu C. , Tirone P. Preclinical profile of Gd-BOPTA. A liver-specific MRI contrast agent. Invest Radiol. 1990; 25 :S59–S60. [PubMed: 2283258]
    23.
    Planchamp C. , Ivancevic M. , Pastor C. , Vallee J. , Pochon S. , Terrier F. , Mayer J. , Reist M. Hollow fiber bioreactor: new development for the study of contrast agent transport into hepatocytes by magnetic resonance imaging. Biotechnol Bioeng. 2004; 85 (6):656–665. [PubMed: 14966807]
    24.
    Planchamp C. , Beyer G. , Slosman D. , Terrier F. , Pastor C. Direct evidence of the temperature dependence of Gd-BOPTA transport in the intact rat liver. Appl Radiat Isot. 2005; 62 (6):943–949. [PubMed: 15799874]
    25.
    Lorusso V. , Arbughi T. , Tirone P. , de Haen C. Pharmacokinetics and tissue distribution in animals of gadobenate ion, the magnetic resonance imaging contrast enhancing component of gadobenate dimeglumine 0.5 M solution for injection (MultiHance). J Comput Assist Tomogr. 1999; 23 :S181–S194. [PubMed: 10608414]
    26.
    Vittadini G. , Felder E. , Tirone P. , Lorusso V. B-19036, a potential new hepatobiliary contrast agent for MR proton imaging. Invest Radiol. 1988; 23 :S246–S248. [PubMed: 3198355]
    27.
    Morisetti A. , Bussi S. , Tirone P. , de Haen C. Toxicological safety evaluation of gadobenate dimeglumine 0.5 M solution for injection (MultiHance), a new magnetic resonance imaging contrast medium. J Comput Assist Tomogr. 1999; 23 :S207–S217. [PubMed: 10608416]
    28.
    Luzzani F. , Cipolla P. , Pelaprat M. , Robert F. , Gotti C. , Tirone P. , de Haen C. Brain penetration and neurological effects of gadobenate dimeglumine in the rat. Acta Radiol. 1997; 38 (2):268–272. [PubMed: 9093163]
    29.
    La Noce A. , Frigeni V. , Filatori I. , Danieli A. , Tirone P. Gadobenate dimeglumine and cerebral glucose metabolism. Continuous monitoring of striatal lactate levels in freely moving rats. Acta Radiol. 2000; 41 (4):394–399. [PubMed: 10937766]
    30.
    Pastor C. , Planchamp C. , Pochon S. , Lorusso V. , Montet X. , Mayer J. , Terrier F. , Vallee J. Kinetics of gadobenate dimeglumine in isolated perfused rat liver: MR imaging evaluation. Radiology. 2003; 229 (1):119–125. [PubMed: 12944603]
    31.
    Port M. , Corot C. , Violas X. , Robert P. , Raynal I. , Gagneur G. How to compare the efficiency of albumin-bound and nonalbumin-bound contrast agents in vivo: the concept of dynamic relaxivity. Invest Radiol. 2005; 40 (9):565–573. [PubMed: 16118549]
    32.
    Runge V. A comparison of two MR hepatobiliary gadolinium chelates: Gd-BOPTA and Gd-EOB-DTPA. J Comput Assist Tomogr. 1998; 22 (4):643–650. [PubMed: 9676461]
    33.
    Spinazzi A. , Lorusso V. , Pirovano G. , Kirchin M. Safety, tolerance, biodistribution, and MR imaging enhancement of the liver with gadobenate dimeglumine: results of clinical pharmacologic and pilot imaging studies in nonpatient and patient volunteers. Acad Radiol. 1999; 6 (5):282–291. [PubMed: 10228617]
    34.
    Rosati G. , Pirovano G. , Spinazzi A. Interim results of phase II clinical testing of gadobenate dimeglumine. Invest Radiol. 1994; 29 :S183–S185. [PubMed: 7928224]
    35.
    Runge V. , Armstrong M. , Barr R. , Berger B. , Czervionke L. , Gonzalez C. , Halford H. , Kanal E. , Kuhn M. , Levin J. , Low R. , Tanenbaum L. , Wang A. , Wong W. , Yuh W. , Zoarski G. A clinical comparison of the safety and efficacy of MultiHance (gadobenate dimeglumine) and Omniscan (Gadodiamide) in magnetic resonance imaging in patients with central nervous system pathology. Invest Radiol. 2001; 36 (2):65–71. [PubMed: 11224753]
    36.
    Runge V. , Parker J. , Donovan M. Double-blind, efficacy evaluation of gadobenate dimeglumine, a gadolinium chelate with enhanced relaxivity, in malignant lesions of the brain. Invest Radiol. 2002; 37 (5):269–280. [PubMed: 11979153]