Part 1: L5, MRI Contrast Agents

Question 1

What types of ligands are used for Gadalinium and why?

Answer 1

• Gd(III) - Lanthanide (no CFSE); require multidentate ligand (think macrocyclic effect)
• Ensuring the ligand wraps around closely and will not dissociate (avoiding toxicity)
• Chelate effect -> entropic stability
• Gd is hard; necessitating soft oxygen donors (lots of carboxyl groups etc)
• Chelates are designed to minimise the toxicity to a biologically tolerable level of LD50 = 10 mmol/kg

Question 2

Effect of aromatic groups on excretion route

Answer 2

• Increasing proportion of hepatic excretion -> hepatobiliary agents
• Often also extends residency time

Question 3

Features of a typical contrast agent

Answer 3

• q = 1 (water terminology)
• 0.5M (extremely high)
• Extremely high osmolality (ionic); typically 7/8x higher than biological salts
• Very good partition coefficients
• Good stability (logK^mL)

Question 4

How are Gd3+ agents typically applied in imaging?

Answer 4

• Dominant class of agents in use/development stem from bulk biodistribution
• Non specific; distribute throughout plasma and interstitial space in the body
• Excreted by kidney with an elimination half life of 1.5hrs

Question 5

Use of Gd agents for imaging blood pool: (including an example)

Answer 5

Blood pool agents…

• Enhance vascular structure for entire period of MRI exam
• A non-invasive alternative for X-ray angiography (can actually be used as an X-ray contrast agent itself)
• Images of enhanced vessels can be obtained easily using intravenous injections of contrast agents rather than arterial injections in low doses
• e.g. MS-325; strong binding to albumin in serum, reduces free concentration available for glomerular filtration in slowing renal excretion rate

Question 6

Gd contrast agents in hepatobiliary imaging: (by what two processes are they hepatobiliary?)

Answer 6

Hepatobiliary agents…

• Hydrophobic groups on metal chelates -> hepatocellular uptake, excretion into bile ducts, gall bladder and intestines
• Aromatic ring gives rise to both albumin binding in serum and liver uptake (with cytosolic binding into hepatocytes)

Question 7

Current classification of contrast agents: (list magnetic properties and biodistribution by technique)

Answer 7

• T1 agents are paramagnetic and biodistribute extracellularly
• T2 and T2* agents are superparamagnetic and biodistriute intravascularly
• CEST agents are diamagnetic (or PARA) and tissue specific

Question 8

Superparamagnetic negative contrast agents:

Answer 8

• Modified T2
• Often nanoparticles (most commonly iron oxides with a permanent magnetic dipole)
• Induce very large field inhomogeneities
• Causing dephasing of neighbouring protons T2 effects
• T2 = specific relaxation
• T2* = includes susceptibility relaxations from additional fields

Question 9

Iron oxide coated NPs

Answer 9

• Very useful for gastric imaging
• Superparamagnetic iron oxide-based colloids consist of nonstoichiometric microcrystalline magnetite cores of Fe3O4
• Coated with dextrans
• After injection, they accumulate in the reticuloendothelial system of the liver and spleen
• Much more effective in MR relaxation that paramagnetic agents

Question 10

CEST contrast agents:

Answer 10

• Chemical exchange saturation transfer -> difference in frequency of localised protons (which isn’t normally considered in typical MRI mechanisms)
• Acting indirectly on exogenous or endogenous compounds; indirectly detected through water signal with modified sensitivity
• Can use to measure biological pH (selective excitation)
• Essentially one foreign proton is influencing the other in the sample then recording it
• Useful in detecting type of tissue present

Question 11

MRI contrast agents are some of the safest ‘drugs’ in use; how can adverse affects still arise?

Answer 11

• Most likely due to the intact, foreign molecule or the small amount of free ligand added in the formulation, both metal ions and ligands tend to be more toxic than their stable chelates

Question 12

Types of CEST:

Answer 12

• PARA (paramagnetic species)
• DiaCEST

Question 13

Key application of CEST:

Answer 13

• Mapping pH using acidity of protons
• Use to map protein density (NH on backbone) -> hard, protein rich tumours can be differentiated from less harmful, soft and fatty tumours -> termed APT (amide proton transfer MRI)
• Could also bind a water on a paramgnetic material and create a target specific agent -> particular AAs, proteins etc -> realistic biologic function