Paramagnetic Contrast Agents First Pass Gadolinium Agents

Currently, seven gadolinium contrast agents are approved in one or more countries of the world and an eighth is in the final stages of the approval process (Fig. 2). Although all are suitable for use in first-pass CE-MRA, few agents are actually approved specifically for this indication. Six of these seven agents possess no capacity for interaction with serum proteins and can be considered "conventional" first generation gadolinium chelates (Fig. 1, column 1; Fig. 2a-f). The seventh agent, gadobenate dimeglumine (Fig. 2g), possesses elevated Tl-relaxivity in blood due to a unique capacity among currently available agents for weak, transient interaction with serum albumin. This agent is the first representative of a new class of second generation gadolinium agents (Fig. 1,column 2).

Gadolinium Contrast Agents with no Capacity for Protein Interaction

The group of "conventional" gadolinium agents includes the first compounds to be developed for MRI some 12-15 years ago (i.e. gadopentetate dimeglumine, gadoterate meglumine, gadoteridol and gadodiamide) plus two newer agents (gadoversetamide and gadobutrol). Among these agents five are available as 0.5 Molar formulations and one, gadobutrol, as a 1.0 Molar formulation. Although differences exist between these agents in terms of molecular structure and chemical and physical properties (Table 1) [4], all are non-specific and extracellular in nature and all are excreted unchanged through the kidneys by glomerular filtration. Furthermore, the T1 relaxation rates of these agents are comparable, falling in the range between 4.3 and 5.6 L/mmol • s-1 [4-7]. The similar concentrations and relaxation properties of these

Fig. 1. Classification scheme for "vascular" MR contrast agents. The paramagnetic gadolinium chelates can be classified according to their degree of protein interaction. The ultra small iron oxide particles are "blood pool agents" which demonstrate long intravascular enhancement. (n.b. The products in italics are still in the developmental phase at the time of writing)

Table 1. Physicochemical characteristics of commercially-available first pass gadolinium-based MR contrast agents

Magnevist StructureLinear Gadolinium Chelates

Table 1. Physicochemical characteristics of commercially-available first pass gadolinium-based MR contrast agents

Characteristic

Magnevist (0.5 mol/L)

Dotarem (0.5 mol/L)

ProHance (0.5 mol/L)

Omniscan (0.5 mol/L)

Gadovist OptiMARK (1.0 mol/L) (0.5 mol/L)

MultiHance (0.5 mol/L)

Molecular structure

Linear, ionic

Cyclic, ionic

Cyclic, non-ionic

Linear, non-ionic

Cyclic, non-ionic

Linear, non-ionic

Linear, ionic

Thermodynamic stability constant (log Keq)

22.1

25.8

23.8

16.9

21.8

16.6

22.6

Osmolality (Osm/kg)

1.96

1.35

0.63

0.65

1.6

1.11

1.97

Viscosity (mPa ■ s at 37°C)

2.9

2.0

1.3

1.4

4.96

2.0

5.3

T1 relaxivity (L/mmol ■ s1), plasma

4.9

4.3

4.6

4.8

5.6

N/A

9.7

N/A = not available

agents generally translate into similar vascular imaging performance when injected at equivalent dose, and, until recently, the choice of which to use was dictated largely by non-radiological factors.

That certain of the "conventional" gadolinium agents might be considered preferable over others for CE-MRA has emerged from the observations of Prince et al. [8] and others [9, 10] who confirmed earlier work [11,12] in noting that gadodi-amide and gadoversetamide interfere with the col-orimetric test for serum calcium, resulting in spurious hypocalcemia in routine clinical laboratory investigations. This was shown to be due to the relatively low stability of these agents compared to the other available gadolinium agents (Table 1)

and, pertinently, was shown to be a greater problem with higher doses and in patients with renal insufficiency [13]. Notably, high doses of conventional gadolinium agents of up to 0.3 mmol/kg have been routinely used in numerous CE-MRA protocols, particularly those involving large vascular territories such as the run-off vessels [9], and those involving MR angiography of the renal arteries - a frequent procedure among patients with renal insufficiency [14-16].

Another recent observation related to gadolinium chelate stability which may influence the choice of contrast agent for MRI procedures in general concerns the issue of gadolinium retention within the body following possible transmetalla-

Do3a Prohance

Fig. 2a-h. Molecular structures of first pass gadolinium contrast agents. a gadopentetate dimeglumine (Gd-DTPA, Magnevist); b gadoterate meglumine (Gd-DOTA, Dotarem); c gadoteridol (Gd-HP-DO3A, ProHance); d gadodiamide (Gd-DT-PA-BMA, Omniscan); egadoversetamide (Gd-DTPA-BMEA, OptiMARK); f gadobutrol (Gd-BT-DO3A, Gadovist); g gadobenate dimeglumine (Gd-BOPTA, MultiHance);h gadotexetate disodium (Gd-EOB-DT-PA, not yet available)

Fig. 2a-h. Molecular structures of first pass gadolinium contrast agents. a gadopentetate dimeglumine (Gd-DTPA, Magnevist); b gadoterate meglumine (Gd-DOTA, Dotarem); c gadoteridol (Gd-HP-DO3A, ProHance); d gadodiamide (Gd-DT-PA-BMA, Omniscan); egadoversetamide (Gd-DTPA-BMEA, OptiMARK); f gadobutrol (Gd-BT-DO3A, Gadovist); g gadobenate dimeglumine (Gd-BOPTA, MultiHance);h gadotexetate disodium (Gd-EOB-DT-PA, not yet available)

Gadovist Structure

tion and the release of free gadolinium3+ ion. In a study of 18 human subjects undergoing hip joint replacement at 3 to 8 days after the administration of a clinical 0.1 mmol/kg dose of either gadoteridol or gadodiamide, Gibby et al. [ 17] found as much as 4.2 times more gadolinium in the bone samples of patients given gadodiamide than in the samples of patients given gadoteridol (1.90 ^g/g versus 0.45 ^g/g, respectively, by ICP-Mass Spectroscopy). Given that free gadolinium is highly toxic and is not readily eliminated from the body, the potential for release from the less stable agents could be considered a cause for concern particularly for patients undergoing frequent contrast-enhanced procedures or contrast procedures at high doses.

Due to the long-standing and comparatively widespread availability of the majority of non-protein interacting agents formulated at 0.5 M, much of the published literature on CE-MRA is based on studies conducted with these agents and most CE-

MRA examinations in routine practice are performed with these agents. However, the frequent need for high doses of up to 0.3 mmol/kg has prompted the development of newer agents with preferential properties for CE-MRA.

A first departure from the traditional 0.5 M formulation is gadobutrol (Fig. 2f) which is the only agent at present to be prepared commercially as a 1.0 M formulation. Like an early non-commercial 1.0 M formulation of gadoteridol [18], on which the molecular structure of gadobutrol is based, the 1.0 M formulation of gadobutrol is feasible due to a satisfactorily low viscosity of the Gd-BT-DO3A chelate. The principal advantage of gadobutrol in CE-MRA is that twice the concentration of gadolinium can be delivered to the vessel of interest per unit volume resulting in a greater intravas-cular signal than is achievable with an equivalent dose of a conventional 0.5 M agent. Alternatively, a lower overall dose can be given enabling a smaller, o o d c o

Fig. 3a, b. Contrast-enhanced MR-angiograms of a 31-year-old male volunteer of 78 kg after (a) Magnevist and (b) Gadovist 1.0. Both contrast agents were administered at a dose of 0.13 mmol/kg bodyweight although the injection rate of the Gadovist-enhanced exam (0.8 ml/s) was half that of the Magnevist-enhanced exam (1.6 ml/s) to ensure identical overall injection times. Both images reveal diagnostic image quality, but the Gadovist 1.0 exam illustrates better delineation of smaller vessels [Images courtesy of Dr. Mathias Goyen, Dept. of Diagnostic and Interventional Radiology, University Hospital Essen, Germany]

Gadolinium Contrast Agent

Fig. 3a, b. Contrast-enhanced MR-angiograms of a 31-year-old male volunteer of 78 kg after (a) Magnevist and (b) Gadovist 1.0. Both contrast agents were administered at a dose of 0.13 mmol/kg bodyweight although the injection rate of the Gadovist-enhanced exam (0.8 ml/s) was half that of the Magnevist-enhanced exam (1.6 ml/s) to ensure identical overall injection times. Both images reveal diagnostic image quality, but the Gadovist 1.0 exam illustrates better delineation of smaller vessels [Images courtesy of Dr. Mathias Goyen, Dept. of Diagnostic and Interventional Radiology, University Hospital Essen, Germany]

more compact bolus which is preferable for maintaining a greater, more prolonged SNR enhancement [19]. Initial studies have shown that gadobutrol is safe [20] and that it may have advantages over conventional agents for total body MRA [21] and for the improved visualization of smaller vessels in the pelvic vasculature [22, 23] (Fig. 3). However, a recent multicenter study to evaluate gadobutrol for the detection of peripheral vascular disease has suggested that whereas comparable image quality to that seen with DSA is achievable in the pelvis and thigh, imaging of the calf muscles with gadobutrol may still be compromised by spatial resolution and technical limitations [24]. On the other hand, many of these problems may be overcome with the use of midfemoral venous compression techniques [25]. Finally, the anticipated benefits of using smaller bolus volumes for improved time-resolved multiphasic pulmonary MRA [3], have not yet been borne out in clinical practice: a recent study comparing gadobutrol with gadopentetate dimeglumine reported no relevant advantages for the former agent and it was concluded that the absence of a significant benefit may have been due to T2/T2* effects caused by the high intravascular concentration at the high injection rate used (5.0 mL/second) [26]. T2/T2* effects may also explain the observed absence of any benefit of gadobutrol over gadopentetate dimeglu-mine in time-resolved multiphasic MRA of the abdomen [27].

Gadolinium Contrast Agents with weak Protein Interaction

A second and more innovative departure from the conventional first generation non-protein interacting gadolinium chelates is gadobenate dimeglu-mine (Fig. 2g). This agent differs from the other available gadolinium agents in that it possesses a higher T1 relaxivity in blood (9.7 L/mmol • s1) due to weak and transient interactions between the Gd-BOPTA chelate and serum proteins, particularly albumin [4,28]. This higher T1 relaxivity manifests as a significantly greater intravascular signal intensity enhancement compared to that achieved with conventional gadolinium chelates at equivalent dose [29,30], with the benefits noted in particular for the visualization of smaller vessels (Fig. 4). Preliminary dose-finding studies in the pelvic and abdominal/renal vasculature established that the optimum dose needed to obtain images of high diagnostic quality was 0.1 mmol/kg bodyweight [31, 32]. A recent intra-individual crossover study in the renal vasculature has demonstrated that the image quality achieved with gadobenate dimeglu-mine at this dose is equivalent to that achieved with gadopentetate dimeglumine at a double dose of 0.2 mmol/kg bodyweight [33] (Fig. 5). The need for only a single 0.1 mmol/kg dose of gadobenate dimeglumine is clearly beneficial in this group of patients with potential renal insufficiency.

The clinical advantages of the increased relax-

Magnevist Injection

Fig. 4a, b. Contrast-enhanced MR-angiograms of a 24-year-old male volunteer of 81 kg after (a) Magnevist and (b) MultiHance. Both contrast agents were administered at a dose of 0.1 mmol/kg bodyweight and at an injection rate of 1.6 ml/s. Both images reveal diagnostic image quality, but the MultiHance exam shows improved delineation of distal vascular segments and smaller vessels in the lower abdomen and pelvis [Images courtesy of Dr. Mathias Goyen, Dept. of Diagnostic and Interventional Radiology, University Hospital Essen, Germany]

Fig. 4a, b. Contrast-enhanced MR-angiograms of a 24-year-old male volunteer of 81 kg after (a) Magnevist and (b) MultiHance. Both contrast agents were administered at a dose of 0.1 mmol/kg bodyweight and at an injection rate of 1.6 ml/s. Both images reveal diagnostic image quality, but the MultiHance exam shows improved delineation of distal vascular segments and smaller vessels in the lower abdomen and pelvis [Images courtesy of Dr. Mathias Goyen, Dept. of Diagnostic and Interventional Radiology, University Hospital Essen, Germany]

Magnevist Injection

Fig. 5a, b. Maximum intensity projection (MIP) reconstructions of the right renal artery after the administration of (a) MultiHance at 0.1 mmol/kg bodyweight and (b) Magnevist at 0.2 mmol/kg bodyweight. Both images reveal a severe proximal stenosis (arrows). The two-fold higher Tl-relaxivity of MultiHance compared to that of Magnevist permits images of equivalent diagnostic quality at a standard dose of 0.1 mmol/kg

Fig. 5a, b. Maximum intensity projection (MIP) reconstructions of the right renal artery after the administration of (a) MultiHance at 0.1 mmol/kg bodyweight and (b) Magnevist at 0.2 mmol/kg bodyweight. Both images reveal a severe proximal stenosis (arrows). The two-fold higher Tl-relaxivity of MultiHance compared to that of Magnevist permits images of equivalent diagnostic quality at a standard dose of 0.1 mmol/kg

Fig. 6a-c. Stenosis of the left carotid artery. The MR-angiogram after 18 ml (0.13 mmol/kg) gadodiamide (Omniscan) (a) reveals a severe stenosis (arroW) of the left internal carotid artery. Conversely, the MR-angiogram after 14 ml (0.1 mmol/kg) gadobenate dimeglumine (MultiHance) (b) reveals only a moderate stenosis (arroW) of the left internal carotid artery. Conventional digital subtraction angiography (c) confirms the presence of only a moderate stenosis of the internal carotid artery [Images courtesy of Prof. Siegfried Thurnher, Dept. of Radiology and Nuclear Medicine, Hospital Brothers of St. John of God, Vienna, Austria]

ivity have been demonstrated for all vascular territories from the carotid vasculature [34, 35] to the distant run-off vessels [36,37]. In the carotid arteries gadobenate dimeglumine - enhanced MRA has been shown to be superior to unenhanced MRA and at least as accurate as conventional DSA for the depiction of carotid artery stenosis [35] (Fig. 6). A major advantage of gadobenate dimeglumine compared to other gadolinium agents, however, is in imaging of the peripheral vasculature and other vascular territories for which a large field of view is required. In imaging of the peripheral run-off vessels, gadobenate dimeglumine has been shown to be superior to both gadopentetate dimeglumine and gadoterate meglumine, particularly for visualization of the vessels of the lower legs [36-38]. It is possible that the benefit with gadobenate dimeg-lumine in more distal vessels is due not only to the increased relaxivity of this agent but also to a reduced rate of extravasation compared to that occurring with other agents due to the weak interaction of the Gd-BOPTA molecule with serum proteins. The weak interaction has previously been postulated to explain a tendency towards increased signal-to-noise (SNR) and contrast-to-noise (CNR) with gadobenate dimeglumine compared to gadopentetate dimeglumine on descending the abdominal aorta [33].

In addition to improved MRA of the vessels of the lower extremities, gadobenate dimeglumine has also been shown to be effective for MRA of the upper extremities [39] and for whole body CE-MRA [40-43]. The higher relaxivity of gadobenate dimeglumine is again beneficial for this latter application in that a dose of only 0.2 mmol/kg body-weight is needed to achieve high quality images from the carotid arteries to the distal run-off vessels [41,43]. Like the conventional non-protein interacting gadolinium chelates, gadobenate dimeg-lumine has an excellent safety profile with a very low incidence of adverse events noted for the clinical development program as a whole and for CE-MRA applications in particular [44].

A second agent with elevated T1 relaxivity (8.2 L/mmol • s-1) in human plasma is gadotexetate disodium (Fig. 2h) [45]. Although not yet approved anywhere for contrast-enhanced MR imaging, it is conceivable this agent may also have advantages over conventional gadolinium agents for CE-MRA. However, all available developmental information concerns the potential of this agent for liver imaging: no data are as yet available concerning its potential for CE-MRA applications.

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  • elanor
    Is mri gadolinium diamagnetic or paramagnetic?
    6 years ago

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