Lecture 21 BIOE 498/598 DP 04/16/2014. Molecular Imaging Modalities. Nuclear medicine - PET - SPECT MRI US Optical (NIRF) CT PAT Dual photon Optical coherence Bioluminescence. PET Cyclotron, Nuclear. Ultra Sound. CT/ SPECT-CT. Optical IVIS (Fluorescence, Luminescence).
Lecture 21BIOE 498/598 DP04/16/2014
Molecular Imaging Modalities
PET Cyclotron, Nuclear
Optical IVIS (Fluorescence, Luminescence)
Tools that enable visualization and quantification in
space and over time of signals from molecular
Characteristics of some Clinically Relevant Imaging Modalities
Why the name change?
most likely explanation:
nuclear has bad implications
History of MRI
Hydrogen nuclei have a quantum physics property called “spin”.
In quantum physics terms, "spin" doesn't mean going round and round.
MRI first “irritates” the hydrogen nuclei and then from their "responses", detects their presence.
The magnetic fields produced by the magnet is represented by the green lines with arrows. This magnetic field is continuously present and in our example, goes from the top to the bottom (direction of arrows).
The magnetic field does something interesting to the spins of the hydrogen nuclei. The magnetic field (green lines) are going from the top to the bottom. The strong magnetic field makes the spins (blue arrows) of the hydrogen nuclei line up along the magnetic field. Some of the hydrogen nuclei line up in the direction of the magnetic field (lower nuclei in diagram) and other hydrogen nuclei line up opposite to the direction of the magnetic field (upper nuclei in diagram)
There are also some hydrogen nuclei that have spins that are in the opposite direction to the magnetic field and have an "higher" energy. Labeled - "high energy nuclei" as "High" .
After the magnetic field has made the nuclear spins line up, there are slightly more low energy nuclei than high energy nuclei.
It is the behavior of these low energy hydrogen nuclei that make MRI possible.
The MRI machine applies a current to this energy producing coil for a short period. During this period, the coil produces energy in the form of a rapidly changing magnetic field (pink waves).
The frequency (i.e. how often it changes in one second) of this changing field falls within the frequency range commonly used in radio broadcasts. Therefore this energy is often called "radio frequency" energy (RF energy) and the coil is often called an radio frequency coil ( RF coil).
The hydrogen nuclei with low energy absorb the energy sent from the RF coil.
The absorption of RF energy changes the energy state of the low energy hydrogen nuclei. Once the low energy nuclei absorb the energy, they change their spin direction and become high energy nuclei.
After a short period, the RF energy is stopped.
The hydrogen nuclei that recently became 'high energy' prefer to go back to their previous, 'low energy' state and they start releasing the energy that was given to them. They release the energy in the form of waves, which in the diagram below, is shown in red.
The MRI machine has "receiver coils " (blue coil shown below) that receive the energy waves sent out by the nuclei. Having given up their energy, the nuclei change their spin direction and return to the low energy state that they were in before.
The receiver coil converts the energy waves into an electrical current signal. In this way, the MRI machine is able to detect hydrogen nuclei in the body.
Basic Physics of MRI
Nuclear magnetic moments precess about B0.
Nuclei spin axis not parallel to B0 field direction.
Basic Physics of MRI
MRI-at a glance
Closed (traditional) MRI
So what are we measuring in MR?
Several processes by which nuclear magnetization prepared in a non-equilibrium state return to the equilibrium distribution.
(how fast spins "forget" the direction in which they are oriented. The rates of this spin relaxation can be measured in both spectroscopy and imaging applications- T1and T2)
What is T1 and T2?
Basic Physics of MRI: T1 and T2
T1 is shorter in fat (large molecules) and longer in CSF (small molecules). T1 contrast is higher for lower TRs.
T2 is shorter in fat and longer in CSF. Signal contrast increased with TE.
Rule of Thumb!
Importance of Exogenous Contrast
MRI has high contrast for different tissue types!
TE = 14 ms
TR = 400 ms
TE = 100 ms
TR = 1500 ms
TE = 14 ms
TR = 1500 ms
Native Tissue Contrast Can Be Altered Pharmacologically
Grey Matter (GM)
White Matter (WM)
Comparison with X-ray Contrast
Concept of Magnetism
Importance of chelates
Source: Joe Gati, photos
Anyone entering the magnet must be metal free
magnetic resonance angiography (MRA).
T1 Contrast Agents
Paramagnetic Contrast Agents: Commercial MRI Agents
Gadobenatedimeglumine is partially taken-up by hepatocytes and excreted via the bile (up to 5% of dose).
The elimination half-life of gadobenatedimeglumine is ~ 1 hour.
It is not metabolized.
The gadobenate ion is excreted predominantly by the kidney; 78% to 96% recovered in the urine.
Small molecule MR contrast agents
Coupling to macromolecules/NP increases relaxivity by slowing the rotation of chelate
Science 7 August 2009: Vol. 325. no.5941, pp. 701 - 704
MS-325 noncovalently couples to albumin
increasing relaxivity from 5 to 50 L (mm*s)-1
Importance of macromolecules
Gadomer-17: A Dendritic Contrast Agent
Gadofluorine Micellar Blood Pool Contrast Agent
Gadomer-17 is a dendritic gadolinium (Gd) chelate carrying 24 Gd ions (G3)
After i.v. injection Gadomer-17 distributes almost exclusively within the intravascular space without significant diffusion into the interstitial space.
After single i.v. injection in rats, the dendritic contrast medium was rapidly and completely eliminated from the body via glomerular filtration.
IR turbo FLASH images before and 48 hours after application of Gadofluorine in 18-month-old WHHL rabbit at identical slice positions
Misselwitz et al Magnetic Resonance Materials in Physics, Biology and Medicine Volume 12, Numbers 2-3 / June, 2001
Barkhausen et al Circulation. 2003;108:605.
T2 Contrast Agents
Superparamagnetic Iron Oxides
A wide variety of iron oxide based nanoparticles have been developed that differ in hydrodynamic particle size and surface coating material (dextran, starch, albumin, silicones)
In general terms, these particles are categorized based upon nominal diameter into superparamagnetic iron oxides (SPIO, 50nm to 500nm) and ultra-small superparamagnetic iron oxides (USPIO, < 50 nm).
Size dictates their physicochemical and pharmacokinetic properties.
USPIO Assessment of Atherosclerotic Plaques
SPIO are Useful For Identifying Hepatic Tumors
Tanimoto et al Organ Microcirculation, 2005
Left: Axial T2-weighted sequence of the liver with high signal metastasis
Right: Signal dropout in the normal liver following infusion of Endorem, (Guerbert, UK), with increased definition of the metastasis
Trivedi et al Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1601.
Cardiovascular MR Imaging
Long waiting time before scanning 24-48h
Colloidal Iron Oxide Nanoparticle (CION)
Cartoon illustrating hypothesis of decreased T2* effects of CION to SPIO
(a) A typical iron oxide particle surrounded by water within a B0 field. The field dependent dipole moment created is shown. Protons pass deep within this magnetic flux field and experience strong dephasing T2 effects. (b). The encapsulation of CION iron crystals reduces the effective field experienced by the surrounding protons, such that the relative impact on T2* is greater than the changes of T1 relaxivity. (c) The encapsulation of CION iron crystals with surfactant cross-linking further reduces the effective field experienced by the surrounding protons, such that the impact on T2* is further increased relative to the changes of T1.
T1 Contrast Agent!
Low susceptibility artifact
Senpan, Pan, Wickline, Lanza, 2009 ACS Nano
In vitro and ex-vivo Targeted MRI
with CION with anti-Fibrin Antibody
Fibrin-rich Plasma Clots
Rapid T1w Imaging
Senpan, Caruthers, Pan, Wickline, Lanza, 2009 ACS Nano
Imaging (1.5T) of Thrombus with PFC NP
High Detection Sensitivity 0.7 x0.7mm
High Contrast and Resolution 0.1 x0.1mm
Canine External Jugular Vein
Human CEA specimen (2h)
High Molecular Relaxivity
Wickline et al J MagnReson Imaging 2007; 25: 667-680
Thrombus in vivo
Unstable Plaque ex vivo
Lanza Wickline Circulation 2001; 104: 1280-1285.
“HOT SPOT” MRI
1H Image (4.7 T)
Quantitative Mapping of Fibrin Binding Sites
19F Projection Image (4.7 T)
[ NP] from 19F spectroscopy
Local nanoparticle concentration
1H image: 256 x 256 matrix; 0.5 s TR; 7.6 ms TE; 1 mm slice thickness; 2 signal averages
19F image: 64 x 32 matrix; 1.0 s TR; 4.5 ms TE; 26 mm slice thickness; 2 signal averages
Quantitative MR Molecular imaging
Neubauer et al J Cardiovasc Magn Reson 2007; 9: 565-573.
Molecular Imaging of avb3 in VX2 In Vivo
3D neovascular maps of example Vx-2 tumors on day 16 following treatment with avb3 -targeted fumagillin nanoparticles (top) vs. avb3 -nanoparticles without drug (bottom).
Note the asymmetric distribution of angiogenic signal (blue) over the tumor surface in both the control and treated animals. Neovessel dense islands and the interspersed fine network of angiogenic proliferation over the tumor surface are diminished in rabbits receiving the targeted fumagillin treatment.
Baseline Images with Regions of Signal Enhancement
at 120 Minutes Overlaid
Integrin homing ligand
αvβ3-targeted peptidomimetic conjugated to PEG(2000)-Phosphatidylethanolamine
Winter et al Cancer Res. 63,5838-5843
Winter et al FASEB Journal. 2008;22:2758-2767.