Computational Chemistry-MRI Notes

 

Magnetic resonance imaging (MRI) is arguably the most sophisticated imaging method used in clinical medicine. In recent years, MRI scans have become increasingly common, as costs decrease.

In this article, we will outline the basic principles behind MRI scans, how to orientate and interpret a scan, and address some of their advantages and disadvantages compared to other imaging modalities.

Basic Principles

MRI scans work as an imaging method due to the unique make-up of the human body. We are comprised entirely of cells which all contain water – principally made of hydrogen ions (H₂O).

The magnet embedded within the MRI scanner can act on these positively charged hydrogen ions (H⁺ ions) and cause them to ‘spin’ in an identical manner. By varying the strength and direction of this magnetic field, we can change the direction of ‘spin’ of the protons, enabling us to build layers of detail.

When the magnet is switched off, the protons will gradually return to their original state in a process known as precession. Fundamentally, the different tissue types within the body return at different rates and it is this that allows us to visualise and differentiate between the different tissues of the body.

 Pulse Radiology Education

Fig 1 – MRI scanning is based on the excitation and relaxation of protons.

Uses of MRI Scanning

Magnetic resonance imaging can produce highly sophisticated and highly detailed images of the human body. Generally speaking, MRI scanning is excellent for visualising soft tissue – and so it is often used in the detection of tumours, strokes and bleeds. It also can be used to visualise the functionality of suspected masses and tumours through IV, gadolinium-based agents.

MRI scans have many advantages. As stated previously, they provide excellent detail of the soft tissues of the body, and they do not cause any radiation exposure to the patient. However, they are time consuming – averaging approximately 35-45 minutes to complete. This limits their use in trauma and emergency situations, where CT scanning is often preferred. They are also by far the most expensive of all the imaging modalities available.

Factor	CT (CT ado used as example)	MRI	X-ray (CXR used as example)	Ultrasound
Duration	3-7 minutes	30-45 min	2-3 min	5-10 minutes
Cost	Cheaper	Expensive	Cheap	Cheap
Dimensions	3	3	2	2
Soft tissue	Poor detail	Excellent detail	Poor detail	Poor detail
Bone	Excellent detail	Poor detail	Excellent detail	Poor detail
Radiation	10mSv	None	0.15mSv	None

At present, there are no known long lasting adverse effects from MRI scans. However, MRI safety has recently become a major focus in hospital and outpatient environments due to the potential attraction to ferromagnetic objects and devices. Some medical and implantable devices are considered contraindications for MRI evaluation – such as cardiac pacemakers, heart monitors, defibrillators and other battery-operated devices.

 

ACTION MECHANISM AND PHARMACOLOGY OF GBCAS

All Gadolinium-Based Contrast Agents (GBCAs) contain the paramagnetic ion of the rare earth metal gadolinium (Gd3+), which possesses the most unpaired electrons of any stable ion (seven), creating a high magnetic moment that is effective at enhancing proton relaxation (Caravan et al., 1999; Lin et al., 20070.Paramagnetic contrast media shorten the T1 (longitudinal) and T2(transversal) relaxation times of surrounding water protons to indirectly produce a signal enhancing effect (Lauffer, 1987). The efficiency of an agent to shorten relaxation times is called relaxivity, which isdependent on the ligand surrounding the Gd3+ ion and influenced by extrinsic factors including temperature,magnetic field strength and the tissue surroundings (water, plasma or blood). At approved clinical doses ofGBCAs (typically between 0.1 and 0.3 mmol/kg body weight), the T1 relativity effect dominates and yields bright contrast (Cheng et al., 2012; Lauffer, 19990).Following intravenous injection, all GBCAs distribute in the blood and extra vascular  –  extracellular space (Aime& Caravan, 2009; Staks et al., 1994). GBCAs are biologically inert and rapidly eliminated by the kidneys, with the exception ofgadoxetic acid(Primovist®/Eovist®), gadobenate dimeglumine (Multihance®) and gadofosveset(Vasovist

®/Ablavar ®), which are in part taken up by hepatocytes and eliminated by the hepatobiliary system.

As Gd3+ ions are toxic, they are chelated with organic ligands to create GBCAs with either a linear ormacrocyclic structure. For GBCAs with a linear structure (e.g., Magenvist, Multi Hance, or Ominscan), a polyamino-carboxylic acid backbone wraps around the Gd 3+ ion, but does not fully enclose it, whereas in macrocyclic chelates (gadobutrol [Gadovist®], gadoterate meglumine[Ddexzotarem®], and gadoteridol [Prohance®]), a rigid ―cage‖ with a preorganized cavity surrounds the ion. The structure of the GBCA determines its complex stability and stability in vivo. An in vitro study mimicking physiological serum conditions in renally impaired subjects demonstrated that linear agents,incubated over a 15-day period, could release substantial amounts of their Gd 3+, while none of the macrocyclic agents (Gadavist, Dotarem, ProHance) showed detectable Gd 3+ release (<0.1% during 15 days of incubation)

(Frenzel et al., 2008). This study also demonstrated that for the macrocyclic agents, charge was not aninfluencing parameter on complex stability. However, in vivo, the majority of a GBCA dose is excreted within afew days, even in renally impaired patients; for example, the elimination half-life of gadobutrol is 90 min inhealthy subjects (Staks et al., 994) and 7 – 26 h in those with kidney disease (Frenzel et al., 2008; Tombach et al.,2000).

 

 

 

 

 

DEVELOPMENT AND CHARACTERISTICS OF MR CONTRAST AGENTS

After the introduction of gadopentetate  dimeglumine, the use of CE-MRI as a diagnostic imaging tool has expanded rapidly. While it was understood that Gd 3+ was the most effective paramagnetic ion for proton relaxation, other paramagnetic ions have been developed for use as MRI contrast agents, including Mn 2+ (Bernardion et al., 1992) and iron oxide compounds (Stark et al., 1988). Today, contrast media are administer edin about 25% of all MRI examinations, especially for the brain and spine, for MR angiography (MRA) and forMRI of the abdomen, breast and heart (Ferre et al., 2012).Five further extracellular GBCAs, exhibiting the same, passive distribution and renal excretion as gadopentetate dimeglumine, have been approved for clinical use (Restrepo et al., 2012; Serrano et al., 2012)gadoterate (1989), gadoteridol (1992), gadodiamide (Omniscan ®; 1993), gadobutrol (1998) and gadoversetamide (Optimark™; 1999). With the approval of gadobenate (1998) and gadoxetic acid (2005), two agents entered the market which exhibited a different pharmacokinetic profile to the other GBCAs—  in addition to extracellular distribution, these agents are taken up to different degrees by hepatocytes, and thus produce a unique enhancement of liver parenchyma with partial excretion in the bile. A third group of agents are those which, after intravenous injection, remain in the circulation for prolonged periods, allowing extend edimaging times for MRA. These agents include gadofosveset and the ultra small superparamagnetic  iron oxide (USPIO) particles (which have limited commercial availability) (Bremerich et al.,2007)Gadolinium-based contrast agents differ in their ability to shorten relaxation times, as a function oftheir relaxivity and local tissue concentration (Rohrer et al., 2005) Gadobutrol was considered a ‗second -generation‘ GBCA (Scott, 2013) owing to its higher concentration and relatively high relaxivity (and thus

improved imaging capacity) compared with earlier agents. (Gadobutrol is the only GBCA formulated at a concentration of 1.0 M, twice that of other agents. Combined with its high relaxivity in plasma, gadobutrol provides the greatest T1 shortening per volume of any currently available GBCA (Sieber, 2009).