Paramagnetic Contrast Agents Blood Pool Contrast Agents

The so-called paramagnetic "blood pool" contrast agents are agents for which the intra-vascular residence time is considerably extended compared to the conventional "first pass only" gadolinium agents. With these agents the intravascular signal remains high for an extended period of time thereby permitting MR imaging during a more prolonged "steady-state" timeframe in addition to conventional first pass CE-MRA. There are two principal types of paramagnetic "blood pool" contrast agent: those whose intravascular residence time is prolonged due to a capacity of the gadolinium chelate for strong interaction with serum proteins, and those that have a macro-molecular structure whose large size limits the extent of extravasation compared to the first pass gadolinium agents. As yet none of these agents are approved for clinical use.

Gadolinium Contrast Agents with strong Protein Interaction

Currently, two agents with strong affinity for serum proteins are undergoing clinical development. The agent furthest along the developmental process is gadofosveset trisodium (MS-325) which has completed Phase II and III clinical trials and has been submitted for FDA approval for use in CE-MRA at a dose of 0.03 mmol/kg bodyweight. This agent has been reported to be 88-96% noncovalently bound to albumin in human plasma and to exhibit a relax-ivity at 0.5T that is 6 to 10 times that of gadopente-tate dimeglumine [46-49]. Studies have shown that this agent can be utilized both for first pass CE-MRA and for steady-state CE-MRA of a number of vascular territories, including the carotid arteries [50], the aortoiliac vasculature (Fig. 7) and the peripheral run-off vessels [48]. Other studies suggest MS-325 may also prove beneficial for CE-MRA of the coronary arteries [51,52].

The second agent with strong affinity for serum proteins is gadocoletic acid (B22956). This agent has completed Phase I trials and is currently undergoing Phase II trials for enhanced coronary MRA. B22596 has been shown to have even stronger affinity for serum albumin than MS-325 (approximately 94% bound noncovalently) and to have a similarly long intravascular residence time [53, 54]. Preliminary studies have shown that a dose of 0.075 mmol/kg B22596 is able to markedly improve visualization of both the left and right coronary artery systems compared to that achievable with state-of-the-art unenhanced 3D coronary MRA techniques [55-57] (Fig. 8). Like MS-325, B22956 can be used to acquire conventional high quality first pass dynamic images in addition to delayed steady state vascular images.

Both these agents appear very promising and have excellent safety profiles.

Gadolinium Contrast Agents with Macro-molecular Structures

Examples of gadolinium-based blood pool agents with macromolecular structures are P792 [58, 59] and gadomer-17 [60, 61]. These agents differ from the currently available low molecular weight gadolinium agents in possessing large molecular structures that prevent extravasation of the molecules from the intravascular space following injection. The molecular weights of P792 and gadomer-17 are 6.5 kDa and 35 kDa, respectively [59, 61], which compare with weights of between approximately 0.56 and 1.0 kDa for the purely first pass gadolinium agents. Whereas the structure of P792 is based on that of gadoterate substituted with four large hydrophilic spacer arms [62], gadomer-17 is a much larger polymer of 24 gadolinium cascades [61]. In addition to differences in molecular weight and structure, these two agents appear to differ in terms of their rates of clearance, with P792 considered a rapid clearance blood pool agent [59, 62]. Despite these differences, both agents are currently under investigation for possible applications in CE-MRA of the coronary arteries [59,61].

Mra Coronary Artery

Fig. 7a, b. MR-an-giograms of the pelvic arteries obtained (a) during the first pass of MS-325 and (b) on steady state MR angiog-raphy. The presence of pelvic artery stenoses (arrows) is evident on both images. [Images courtesy of EPIX Medical, Cambridge, Massachusetts, USA, Schering AG, Berlin, Germany; Mathias Goyen, University Hospital Essen, Essen/ Germany, and Steven D. Wolff, Cardiovascular Research Foundation, New York, USA]

Coronary Artery Mra

Fig. 8a-d. Coronary MRA of RCA. a T2 prep coronary artery imaging (standard sequence). b Intravascular contrast enhancement using B22956 in combination with an inversion-recovery sequence. c3D volume rendered MRA of the RCA (d) conventional x-ray angiography. Multiplanar reformatted 3 D images ("soap-bubble reconstruction") showing the effect of intravascular contrast enhancement (b) in comparison with the standard, non-contrast enhanced imaging approach (a). Note the postcontrast increase in vessel sharpness, visible vessel length and the highly efficient suppression of signal from surrounding tissue, thereby facilitating clear visualization of the RCA. 3 dimensional volume rendered coronary MRA of a non-diseased RCA (c) in comparison with conventional x-ray angiography (d). The intense signal from the coronary artery lumen due to intravascular contrast enhancement allows visualization of the RCA far beyond the crux and improves visibility of coronary side branches. [Images (a), (b) and (d) courtesy of Dr. Eike Nagel, Clinic of Internal Medicine/Cardiology, German Heart Institute, Berlin, Germany. Image (c) courtesy of Dr. I. Paetsch, Clinic of Internal Medicine/Cardiology, German Heart Institute, Berlin, Germany]

Fig. 8a-d. Coronary MRA of RCA. a T2 prep coronary artery imaging (standard sequence). b Intravascular contrast enhancement using B22956 in combination with an inversion-recovery sequence. c3D volume rendered MRA of the RCA (d) conventional x-ray angiography. Multiplanar reformatted 3 D images ("soap-bubble reconstruction") showing the effect of intravascular contrast enhancement (b) in comparison with the standard, non-contrast enhanced imaging approach (a). Note the postcontrast increase in vessel sharpness, visible vessel length and the highly efficient suppression of signal from surrounding tissue, thereby facilitating clear visualization of the RCA. 3 dimensional volume rendered coronary MRA of a non-diseased RCA (c) in comparison with conventional x-ray angiography (d). The intense signal from the coronary artery lumen due to intravascular contrast enhancement allows visualization of the RCA far beyond the crux and improves visibility of coronary side branches. [Images (a), (b) and (d) courtesy of Dr. Eike Nagel, Clinic of Internal Medicine/Cardiology, German Heart Institute, Berlin, Germany. Image (c) courtesy of Dr. I. Paetsch, Clinic of Internal Medicine/Cardiology, German Heart Institute, Berlin, Germany]

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