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236
SAINI
AJA:156,
February 1991
Principles Sanjay
Saini
In this section, I briefly review the principles of pharmaceutical manipulation of soft-tissue contrast in MR images and outline the spectrum of MR contrast agents that are undergoing or are close to undergoing clinical evaluation. For a more detailed explanation, a recent review by Lauffer [1] is recommended. MR Contrast
Agents
and Proton
Relaxation
Tissue relaxation times (Ti and T2) and proton density are the principal intrinsic factors that determine signal intensity on MR images. Stated simply, magnetopharmaceuticals manifest their effect on MR images by either decreasing proton relaxation times or by altering proton density. Most of the research effort has centered on the development of magnetopharmaceuticals that decrease proton relaxation times. This phenomenon was first reported more than 40 years ago by Bloch et al. [2], who described the use of paramagnetic ferric nitrate to shorten relaxation times of water protons. The ability of certain chemicals to enhance proton relaxation rates is based on their magnetic response to an external magnetic environment [3], because substances with large magnetic moments (compared with the nuclear magnetic moment of protons) influence relaxation behavior of nearby protons. When classified on the basis of magnetic properties, paramagnetic and ferromagnetic (of which superparamagnetic is a subvariety) materials are the two principal types of MR contrast media. The active ingredients in most paramagnetic contrast agents are paramagnetic ions that have unpaired outer shell electrons, and these contrast agents incorporate one or more paramagnetic metal ions. Of these, paramagnetic gadolinium (111)-with seven unpaired electrons-in gadopentetate dimeglumine is the most widely recognized. Ferromagnetic materials (or one of the subvaneties) consist of paramagnetic ions that are arranged in a crystalline matrix. Paramagnetic iron in crystalline iron oxide is a prototypic example of a superparamagnetic contrast agent. Superparamagnetic materials are potent contrast agents because their magnetization is several orders of magnitude greater than the magnetization of paramagnetic materials. Thus, for example, superparamagnetic contrast agents alter MR signal intensity in doses that are a fraction of doses required for paramagnetic contrast agents. When MR contrast agents bearing large magnetic moments are found in the vicinity of tissue protons (proximity is essential because magnetic strength decreases with distance), they can stimulate nuclear relaxation and thereby decrease both Ti and T2 relaxation times. How do these powerful magnets alter proton relaxation? T2 shortening is easier to envision. Increases in local magnetic field inhomogeneities enhance
dephasing of nonstationary protons, resulting in decreased T2 or T2*. On the other hand, enhanced Ti relaxation occurs when the frequency of time-varying magnetic fields produced by contrast agents (a result of molecular rotation or tumbling) is similar to protons’ resonance (Larmor) frequency. This mechanism is often referred to as dipole-dipole interaction. As paramagnetic ion-chelate complexes increase magnetic field inhomogeneities and also have tumbling rates that approximate Larmor frequency, they produce both T2 and Ti shortening [4]. On the other hand, large particulate magnetized spheres of superparamagnetic contrast agents produce little Ti shortening but preferentially shorten tissue T2 [5]. Instrument
Factors
In MR imaging, reduced Ti increases tissue signal intensity whereas T2 shortening decreases tissue signal intensity. As Ti and T2 shortening have opposing effects on MR images, MR contrast agents are designed, or are administered in doses, so that the effect of one of these concurrent processes predominates. Several instrument factors play an important role in determining which of these effects predominates. These include pulse-sequence timing parameters and field strength. Of these, pulse-sequence timing parameters are of critical importance. For example, because superparamagnetic iron oxide preferentially shortens T2, tissue signal intensity decreases after iron oxide administration, an effect that is best seen on T2-weighted images. Conversely, at recommended doses paramagnetic gadopentetate dimeglumine produces a much larger effect on Ti than on T2. Thus tissue signal intensity increases after gadopentetate dimeglumine is administered, an effect that is best seen on Ti -weighted images. However, in sufficiently high tissue concentrations (such as in the renal collecting system), T2 shortening from gadopentetate dimeglumine is of greater consequence then Ti shortening, which leads to a loss in signal intensity. This effect is best seen on T2-weighted images. Thus, MR contrast agents are often also classified according to their effect on MR images, namely Ti agents, which enhance signal intensity, or T2 agents, which diminish signal intensity. However, this classification is of limited usefulness because some magnetopharmaceuticals fall into either category depending on the MR imaging technique that is used. The effect of static magnetic field on the relaxivity of MR contrast agents is of less practical significance because, in a given setting, this instrument parameter cannot be altered. However, it is important to recognize that the potencies of MR contrast agents depend on field strength. Nuclear magnetic relaxation dispersion (NMRD) studies have shown, for example, that the relaxivity of gadopentetate dimeglumine
Downloaded from www.ajronline.org by 117.255.254.155 on 10/20/15 from IP address 117.255.254.155. Copyright ARRS. For personal use only; all rights reserved
AJA:156, February 1991
ADVANCES
IN CONTRAST-ENHANCED
diminishes by about one third as field strength is varied from 0.02 to i .50 T [6]. Furthermore, at field strengths less than 0.i 5 T, Gd-DOTA (gadolinium tetra-azacyclododecane tetraacetic acid) meglumine is a better Ti relaxation agent than is gadopentetate dimeglumine. Thus the application of contrast agents may not be readily transposed from one field strength to another [7]. Classification
of MR Contrast
Agents
Because of the multitude of contrast agents being developed, a useful classification is one that is based on their physiologic behavior. In this section, the design and pharmacokinetics of MR contrast agents that have undergone or are approaching clinical evaluation is reviewed. Extracellular
Agents
Metal ions chelated to molecules make up a group of contrast agents that have no tissue specificity. Metal ions are chelated to reduce biologic toxicity, and it is the ligand’s biodistribution that determines the pharmacokinetics of the contrast agent. Paramagnetic gadopentetate dimeglumine (Berlex Laboratories, Cedar Knolls, NJ) is the prototypic example of this category of MR contrast agents [8]. Others that have undergone clinical evaluation include Gd-DOTA meglumine (Guerbet Laboratories, Aulnay-sous-Bois, France) [9] and Ferrioxamine (Salutar, Sunnyvale, CA) [1 0]. The physiologic behavior (extracellular distribution) of these contrast agents differs slightly from one to another, except that Ferrioxamine has a slightly higher hepatic excretion [i 0]. However, some magnetic and biochemical differences are present. For example, Ferrioxamine is a weaker Ti agent than gadopentetate dimeglumine is (relaxivity at 20 MHz, i .8 vs 4.5 mmor1 sec1) [10], whereas Gd-DOTA meglumine has a stronger ion-chelate bond than gadopentetate dimeglumine does (K 1 028 vs i 023), resulting in a higher LD50 (5.5 vs i 0.6 mmol/kg) [9]. In practice however, the imaging effects of extracellular contrast agents are similar, and in the discussions that follow, gadopentetate dimeglumine, Gd-DOTA meglumine, and other similar formulations may be interchanged. Gadopentetate dimeglumine administered IV has a plasma half-life of 90 mm, and over 90% is eliminated by the kidneys within 3 hr. Recommended dose in the United States is 0.i mmol/kg, whereas in Europe it may be administered at up to 0.2 mmol/kg. In clinical studies to date, this magnetopharmaceutical has been extremely safe and very few moderate or severe reactions have been attributed to it [i 1 ]. Although it is suggested that gadopentetate dimeglumine should be infused slowly (over several minutes), anecdotal experience and animal studies have shown no increase in reactions with rapid bolus administration [i 2]. To reduce reactions attributable to the hyperosmolar nature of Gd-DTPA dimeglumine, isosmolar nonionic formulations (Gd-DTPA-bis-methylamide (Salutar) [i 3]; Gd-HP-DO3A (Squibb, Princeton, NJ) [i 4]) also have been designed, and clinical trials are in progress. The imaging effects of extracellular contrast agents are identical to those of iodinated contrast media. They are rapidly redistributed from the vascular compartment into the extracellular space and undergo renal elimination by passive gb-
MR
IMAGING
237
merular filtration. On Ti -weighted images, they enhance tissue signal intensity by tissue perfusion or because of breakdown of the blood brain barrier (BBB). With fast T2-weighted gradient-echo (GRE) pulse sequences, decrease in tissue signal intensity from T2 effects can be seen during the first pass of a compact bolus [1 5] or after hyperconcentration in the renal collecting system. Among agents mentioned, Ferrioxamine has been investigated primarily in the urinary tract because of its less potent paramagnetic effect. Hepatobiliary
Contrast
Agents
Efforts to design contrast agents for the hepatobiliary system are based on the chelation of paramagnetic ions to ligands having affinity for hepatocytes. Paramagnetic iron(llI)ethylene-bis-(2-hydroxyphenylglycine) (Fe-EHPG) was the first such agent evaluated in animals [i 6]. However, because only a small percentage of Fe-EHPG is eliminated by hepatocytes, the agent never progressed to clinical trials. Ferrioxamine with less than 20% hepatic excretion has been evaluated clinically; however, it also does not appreciably enhance the liver or biliary tree [i 0]. Newer formulations, such as paramagnetic manganese dipyridoxal diphosphate (MnDPDP, Salutar [i 7]) and an octadentate chelate of gadolinium (B-i 9036, Bracco, Italy [i 8]), both of which have relatively greater hepatobiliary excretion, are more likely to achieve desirable levels of selective hepatobiliary enhancement. For example, approximately 40% B-i 9036 administered IV is excreted into the bile (vs
236
SAINI
AJA:156,
February 1991
Principles Sanjay
Saini
In this section, I briefly review the principles of pharmaceutical manipulation of soft-tissue contrast in MR images and outline the spectrum of MR contrast agents that are undergoing or are close to undergoing clinical evaluation. For a more detailed explanation, a recent review by Lauffer [1] is recommended. MR Contrast
Agents
and Proton
Relaxation
Tissue relaxation times (Ti and T2) and proton density are the principal intrinsic factors that determine signal intensity on MR images. Stated simply, magnetopharmaceuticals manifest their effect on MR images by either decreasing proton relaxation times or by altering proton density. Most of the research effort has centered on the development of magnetopharmaceuticals that decrease proton relaxation times. This phenomenon was first reported more than 40 years ago by Bloch et al. [2], who described the use of paramagnetic ferric nitrate to shorten relaxation times of water protons. The ability of certain chemicals to enhance proton relaxation rates is based on their magnetic response to an external magnetic environment [3], because substances with large magnetic moments (compared with the nuclear magnetic moment of protons) influence relaxation behavior of nearby protons. When classified on the basis of magnetic properties, paramagnetic and ferromagnetic (of which superparamagnetic is a subvariety) materials are the two principal types of MR contrast media. The active ingredients in most paramagnetic contrast agents are paramagnetic ions that have unpaired outer shell electrons, and these contrast agents incorporate one or more paramagnetic metal ions. Of these, paramagnetic gadolinium (111)-with seven unpaired electrons-in gadopentetate dimeglumine is the most widely recognized. Ferromagnetic materials (or one of the subvaneties) consist of paramagnetic ions that are arranged in a crystalline matrix. Paramagnetic iron in crystalline iron oxide is a prototypic example of a superparamagnetic contrast agent. Superparamagnetic materials are potent contrast agents because their magnetization is several orders of magnitude greater than the magnetization of paramagnetic materials. Thus, for example, superparamagnetic contrast agents alter MR signal intensity in doses that are a fraction of doses required for paramagnetic contrast agents. When MR contrast agents bearing large magnetic moments are found in the vicinity of tissue protons (proximity is essential because magnetic strength decreases with distance), they can stimulate nuclear relaxation and thereby decrease both Ti and T2 relaxation times. How do these powerful magnets alter proton relaxation? T2 shortening is easier to envision. Increases in local magnetic field inhomogeneities enhance
dephasing of nonstationary protons, resulting in decreased T2 or T2*. On the other hand, enhanced Ti relaxation occurs when the frequency of time-varying magnetic fields produced by contrast agents (a result of molecular rotation or tumbling) is similar to protons’ resonance (Larmor) frequency. This mechanism is often referred to as dipole-dipole interaction. As paramagnetic ion-chelate complexes increase magnetic field inhomogeneities and also have tumbling rates that approximate Larmor frequency, they produce both T2 and Ti shortening [4]. On the other hand, large particulate magnetized spheres of superparamagnetic contrast agents produce little Ti shortening but preferentially shorten tissue T2 [5]. Instrument
Factors
In MR imaging, reduced Ti increases tissue signal intensity whereas T2 shortening decreases tissue signal intensity. As Ti and T2 shortening have opposing effects on MR images, MR contrast agents are designed, or are administered in doses, so that the effect of one of these concurrent processes predominates. Several instrument factors play an important role in determining which of these effects predominates. These include pulse-sequence timing parameters and field strength. Of these, pulse-sequence timing parameters are of critical importance. For example, because superparamagnetic iron oxide preferentially shortens T2, tissue signal intensity decreases after iron oxide administration, an effect that is best seen on T2-weighted images. Conversely, at recommended doses paramagnetic gadopentetate dimeglumine produces a much larger effect on Ti than on T2. Thus tissue signal intensity increases after gadopentetate dimeglumine is administered, an effect that is best seen on Ti -weighted images. However, in sufficiently high tissue concentrations (such as in the renal collecting system), T2 shortening from gadopentetate dimeglumine is of greater consequence then Ti shortening, which leads to a loss in signal intensity. This effect is best seen on T2-weighted images. Thus, MR contrast agents are often also classified according to their effect on MR images, namely Ti agents, which enhance signal intensity, or T2 agents, which diminish signal intensity. However, this classification is of limited usefulness because some magnetopharmaceuticals fall into either category depending on the MR imaging technique that is used. The effect of static magnetic field on the relaxivity of MR contrast agents is of less practical significance because, in a given setting, this instrument parameter cannot be altered. However, it is important to recognize that the potencies of MR contrast agents depend on field strength. Nuclear magnetic relaxation dispersion (NMRD) studies have shown, for example, that the relaxivity of gadopentetate dimeglumine
Downloaded from www.ajronline.org by 117.255.254.155 on 10/20/15 from IP address 117.255.254.155. Copyright ARRS. For personal use only; all rights reserved
AJA:156, February 1991
ADVANCES
IN CONTRAST-ENHANCED
diminishes by about one third as field strength is varied from 0.02 to i .50 T [6]. Furthermore, at field strengths less than 0.i 5 T, Gd-DOTA (gadolinium tetra-azacyclododecane tetraacetic acid) meglumine is a better Ti relaxation agent than is gadopentetate dimeglumine. Thus the application of contrast agents may not be readily transposed from one field strength to another [7]. Classification
of MR Contrast
Agents
Because of the multitude of contrast agents being developed, a useful classification is one that is based on their physiologic behavior. In this section, the design and pharmacokinetics of MR contrast agents that have undergone or are approaching clinical evaluation is reviewed. Extracellular
Agents
Metal ions chelated to molecules make up a group of contrast agents that have no tissue specificity. Metal ions are chelated to reduce biologic toxicity, and it is the ligand’s biodistribution that determines the pharmacokinetics of the contrast agent. Paramagnetic gadopentetate dimeglumine (Berlex Laboratories, Cedar Knolls, NJ) is the prototypic example of this category of MR contrast agents [8]. Others that have undergone clinical evaluation include Gd-DOTA meglumine (Guerbet Laboratories, Aulnay-sous-Bois, France) [9] and Ferrioxamine (Salutar, Sunnyvale, CA) [1 0]. The physiologic behavior (extracellular distribution) of these contrast agents differs slightly from one to another, except that Ferrioxamine has a slightly higher hepatic excretion [i 0]. However, some magnetic and biochemical differences are present. For example, Ferrioxamine is a weaker Ti agent than gadopentetate dimeglumine is (relaxivity at 20 MHz, i .8 vs 4.5 mmor1 sec1) [10], whereas Gd-DOTA meglumine has a stronger ion-chelate bond than gadopentetate dimeglumine does (K 1 028 vs i 023), resulting in a higher LD50 (5.5 vs i 0.6 mmol/kg) [9]. In practice however, the imaging effects of extracellular contrast agents are similar, and in the discussions that follow, gadopentetate dimeglumine, Gd-DOTA meglumine, and other similar formulations may be interchanged. Gadopentetate dimeglumine administered IV has a plasma half-life of 90 mm, and over 90% is eliminated by the kidneys within 3 hr. Recommended dose in the United States is 0.i mmol/kg, whereas in Europe it may be administered at up to 0.2 mmol/kg. In clinical studies to date, this magnetopharmaceutical has been extremely safe and very few moderate or severe reactions have been attributed to it [i 1 ]. Although it is suggested that gadopentetate dimeglumine should be infused slowly (over several minutes), anecdotal experience and animal studies have shown no increase in reactions with rapid bolus administration [i 2]. To reduce reactions attributable to the hyperosmolar nature of Gd-DTPA dimeglumine, isosmolar nonionic formulations (Gd-DTPA-bis-methylamide (Salutar) [i 3]; Gd-HP-DO3A (Squibb, Princeton, NJ) [i 4]) also have been designed, and clinical trials are in progress. The imaging effects of extracellular contrast agents are identical to those of iodinated contrast media. They are rapidly redistributed from the vascular compartment into the extracellular space and undergo renal elimination by passive gb-
MR
IMAGING
237
merular filtration. On Ti -weighted images, they enhance tissue signal intensity by tissue perfusion or because of breakdown of the blood brain barrier (BBB). With fast T2-weighted gradient-echo (GRE) pulse sequences, decrease in tissue signal intensity from T2 effects can be seen during the first pass of a compact bolus [1 5] or after hyperconcentration in the renal collecting system. Among agents mentioned, Ferrioxamine has been investigated primarily in the urinary tract because of its less potent paramagnetic effect. Hepatobiliary
Contrast
Agents
Efforts to design contrast agents for the hepatobiliary system are based on the chelation of paramagnetic ions to ligands having affinity for hepatocytes. Paramagnetic iron(llI)ethylene-bis-(2-hydroxyphenylglycine) (Fe-EHPG) was the first such agent evaluated in animals [i 6]. However, because only a small percentage of Fe-EHPG is eliminated by hepatocytes, the agent never progressed to clinical trials. Ferrioxamine with less than 20% hepatic excretion has been evaluated clinically; however, it also does not appreciably enhance the liver or biliary tree [i 0]. Newer formulations, such as paramagnetic manganese dipyridoxal diphosphate (MnDPDP, Salutar [i 7]) and an octadentate chelate of gadolinium (B-i 9036, Bracco, Italy [i 8]), both of which have relatively greater hepatobiliary excretion, are more likely to achieve desirable levels of selective hepatobiliary enhancement. For example, approximately 40% B-i 9036 administered IV is excreted into the bile (vs
