The clinical application of macromolecular gadolinium (Gd) complexes as MRI contrast agents is limited by the slow excretion of Gd(III) complexes and consequent long-term tissue accumulation of toxic Gd ions. To alleviate the problem of slow excretion, biodegradable polydisulfide-based macromolecular Gd(III) complexes were designed and prepared based on the disulfide-thiol exchange to allow degradation of the macromolecules by endogenous thiols and to facilitate excretion of Gd(III) complexes after the MRI examination. The in vitro degradation study showed that the polydisulfide agent was readily degraded by cysteine at plasma thiol concentrations. No cross-reaction was observed between the cysteine-34 on human serum albumin (HSA) with the agent. Concentration-dependent blood pool contrast enhancement was observed for the polydisulfide agents. The agents of both high molecular weight (35,000 Da) and low molecular weight (17,700 Da) produced significant contrast enhancement in the heart and aorta in rats at relatively high doses. Except for the bladder, the signal intensities gradually decreased over time. Significant blood pool contrast enhancement was also observed for the high molecular weight agent at a low dose (0.03 mmol-Gd/kg), but not for the agent with a lower molecular weight. The contrast enhancement in the urinary bladder increased over time for the polydisulfide agents and Gd(III)-(DTPA-BMA). Degradation products were identified by mass spectrometry in the urine samples from the rats administered with both polydisulfide agents, which confirmed that the polydisulfide agents were degraded in vivo and excreted through renal filtration. The preliminary results demonstrated the in vitro and in vivo degradability, superior blood pool contrast enhancement, and rapid clearance through renal filtration of the novel biodegradable macromolecular agent. This agent has a great potential for further preclinical and clinical development with application in contrast-enhanced blood pool and cancer MR imaging.

Profound arthrotropism of macromolecules in the AIA rat model was demonstrated with various imaging tools. These observations should help in the conceptual and practical design of novel macromolecular delivery systems for the imaging and treatment of rheumatoid arthritis.

The clinical application of macromolecular Gd(III) complexes as MRI contrast agents is impeded by their slow excretion and potential toxicity due to the release of Gd(III) ions caused by the metabolism of the agents. A polymer Gd(III) chelate conjugate with a cleavable spacer has been designed to solve this problem. Poly(l-glutamic acid)-cystamine-[Gd(III)-DOTA] was prepared by the conjugation of DOTA to PGA (MW = 50,000) via cystamine, a cleavable disulfide spacer, followed by the complexation with GdCl(3). A Gd(III) DOTA chelate derivative was readily released from the polymer conjugate in the incubation with cysteine, an endogenous plasma thiol. The conjugate produced significant MRI blood pool contrast enhancement in nude mice bearing OVCAR-3 human ovarian carcinoma xenographs. Less significant contrast enhancement was observed for a small molecular contrast agent, Gd(DTPA-BMA). The pharmacokinetic MRI study showed that the Gd(III) chelate from the conjugate accumulated in the urinary bladder in a similar kinetic pattern to Gd(DTPA-BMA), suggesting that the chelate was released by the endogenous thiols and excreted through renal filtration. The preliminary results suggest that this novel design has a great potential to solve the safety problem of macromolecular MRI contrast agents.

Three-dimensional fast spin-echo (3DFSE) techniques are promising for black-blood imaging of cerebral vessels. In this study, flow-related signal dephasing was demonstrated as the primary mechanism for blood signal attenuation. Parameter optimization of TR (1500 to 3000 ms), receiver bandwidth (25 to 31.25 kHz), effective TE (25.7 to 30.1 ms), and ETL (7 to 8) was accomplished by making measurements of vessel-to-tissue contrast-to-noise ratios on vessels. A comparison of high-resolution 3DFSE and 3DTOF magnetic resonance angiography demonstrated that 3DFSE can generate images with equivalent or better small vessel detail than conventional techniques. 3DFSE black-blood techniques may provide improved sensitivity of small arteries and veins with slow or in-plane flow and immunity to flow-related distortions. Future studies with optimized parameters will determine the clinical efficacy of this technique.

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The loss of blood vessel visibility due to the signal saturation of slow flow can be partially overcome by the T1 reduction that occurs with the use of contrast agents such as Gd-DTPA during magnetic resonance angiography (MRA) studies. Dynamic-imaging techniques that have been applied successfully in abdominal imaging may also be useful for intracranial applications. However, the time between arterial and venous enhancement is very short during intracranial circulation. This limits the spatial resolution that can be obtained between arterial and venous enhancement. Fortunately, the blood-brain barrier and the relatively long duration of significant decrease in blood T1 has led to the development of very high resolution intracranial MRA techniques. Knowledge of the contrast-agent dilution factors and the ultimate resulting relaxation rates can be used to optimize the imaging parameters to maximize vessel signal relative to the background signal (the signal-difference-to-noise ratio). The additional venous vascular detail in the contrast-enhanced study can be spatially resolved in the 3D image data and determined by incorporating information from both high-resolution precontrast and postcontrast studies. In this article, the history, development and application of contrast agents in MRA are presented.

In this study, the problem of small vessel visualization in magnetic resonance angiography is addressed. The loss of vessel contrast due to slow flow-related signal saturation can be compensated by the T1 reduction obtained from the use of an MR contrast agent, such as Gd-DTPA. The vessel/background signal-difference-to-noise ratio (SDNR) is shown to strongly depend on the imaging parameters, as well as on the time course of the blood T1 values obtained from the contrast injection. Specifically, it was found that vessel SDNR increases almost linearly with TR, if the sampling bandwidth is reduced proportionately.

Fast spin-echo (FSE) imaging techniques are very sensitive to the relative phase between the 90 degrees (excitation) RF pulse and the 180 degrees (refocusing) RF pulses. In this paper, it is demonstrated that a phase shift can be created between the excitation and refocusing pulses in such a manner that the received signal is divided into two components of distinctly different phase shifts. The nature of these two components is reviewed. It is demonstrated that ghosting artifacts will occur when images are reconstructed from this received signal. The ghosting is shown to be object dependent. A correction technique is presented which calculates the phase errors among different echoes based on measurements from a single echo train acquired without phase encoding gradients. The results in both phantom and human studies show that this method is capable of reducing the ghosting artifact in thin slice FSE images.