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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).

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Molecular Imaging Modalities

  • Nuclear medicine
  • - PET
  • - SPECT
  • MRI
  • US
  • Optical (NIRF)
  • CT
  • PAT
  • Dual photon
  • Optical coherence
  • Bioluminescence

PET Cyclotron, Nuclear

Ultra Sound


Optical IVIS (Fluorescence, Luminescence)

Tools that enable visualization and quantification in

space and over time of signals from molecular

imaging agents



Characteristics of some Clinically Relevant Imaging Modalities








Poor depth





Why the name change?

most likely explanation:

nuclear has bad implications

History of MRI

  • NMR = nuclear magnetic resonance
  • nuclear: properties of nuclei of atoms
  • magnetic: magnetic field required
  • resonance: magnetic field x radio frequency
    • 1946: Bloch and Purcell
    • atomic nuclei absorb and re-emit radio
    • frequency energy
    • 1992: Ogawa and colleagues
    • first functional images using BOLD signal





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

  • Nuclei line up with magnetic moments either in a parallel or anti-parallel configuration.
  • In body tissues more line up in parallel creating a small additional magnetization M in the direction of B0.

Nuclear magnetic moments precess about B0.

Nuclei spin axis not parallel to B0 field direction.


Basic Physics of MRI

NMRable Nuclei

  • Body 1H content is high due to water (>67%)
  • Hydrogen protons in mobile water are primary source of signals in fMRI and aMRI

MRI-at a glance

  • Magnetic nuclei are abundant in the human body (H, C, Na, P, K)
  • Since most of the body is H2O, the Hydrogen nucleus is especially prevalent
  • Patient is placed in a static magnetic field
  • Magnetized protons (H nuclei) in the patient align in this field
  • Radio frequency (RF) pulses create oscillating magnetic field perpendicular to static field
  • Magnetic nuclei absorb the RF energy and enter an excited state
  • When the magnet is turned off, excited nuclei return to normal state & give off RF energy
  • Different elements absorb & give off different amounts of RF energy (different resonances)
  • The RF energy given off is picked up by the receiver coil & transformed into images
  • MRI offers the greatest “contrast” in tissue imaging technology
  • cost: about $1250 - $1600
  • time: 30 minutes - 2 hours, depending on the type of study being done

Closed (traditional) MRI

Open MRI


So what are we measuring in MR?

  • Relaxivity!
  • What is a relaxivity?

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?

  • T1-Relaxation: Recovery
    • Recovery of longitudinal orientation of M along z-axis.
    • ‘T1 time’ refers to time interval for 63% recovery of longitudinal magnetization.
    • Spin-Lattice interactions.
  • T2-Relaxation: Dephasing
    • Loss of transverse magnetization Mxy.
    • ‘T2 time’ refers to time interval for 37% loss of original transverse magnetization.
    • Spin-spin interactions, and more.

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.

  • TR determines T1 contrast
  • TE determines T2 contrast.

Rule of Thumb!

  • T1 relaxivity

Bright signal

  • T2 relaxivity

Dark signal

mr manipulation of inherent tissue contrast
MR Manipulation of Inherent Tissue Contrast

Importance of Exogenous Contrast



MRI has high contrast for different tissue types!

Post-Gd T1

T1 Contrast

TE = 14 ms

TR = 400 ms

T2 Contrast

TE = 100 ms

TR = 1500 ms

Proton Density

TE = 14 ms

TR = 1500 ms


T1 (ms)

T2 (ms)

Native Tissue Contrast Can Be Altered Pharmacologically

Grey Matter (GM)



White Matter (WM)






Cerebrospinal Fluid










Comparison with X-ray Contrast

  • In radiography (barium enema, UGI series, angiography, arthrography, etc.) we image the contrast agent itself.
  • In MR we usually do not image the contrast agent itself, but we image the water near the contrast agent that is affected by the contrast agent.
  • Contrast agents change the T1 of the water around them.

Importance of chelates

  • Chelate means “claw”
  • Chelates surround an ion an make a cage around it
  • A chelate of gadolinium occupies all available space around the ion except one
  • Water molecules exchange in and out of that one spot. When in that spot, the spins have an extremely short T1. This accelerates the overall relaxation rate, shortening T1.



Equipments Needed

3T magnet

RF Coil

gradient coil



Gradient Coil

RF Coil

Source: Joe Gati, photos


The Magnet

  • Main field = B0
  • Continuously on
  • Very strong :
  • Earth’s magnetic field = 0.5 Gauss / 1 Tesla (T) = 10,000 Gauss
    • 3 Tesla = 3 x 10,000  0.5 = 60,000 x Earth’s magnetic field




Things fly!

Anyone entering the magnet must be metal free



  • Excellent anatomical detail especially of soft


  • Visualizes blood vessels without contrast:

magnetic resonance angiography (MRA).

  • Intravenous contrast utilized much less frequently than CT.


  • High operating costs.
  • Poor images of lung fields.
  • Inability to show calcification with accuracy.
  • Slow

Paramagnetic Contrast Agents: Commercial MRI Agents

  • The first agent to be developed, gadopentetatedimeglumine (Magnevist): Linear structure & ionic
  • Followed in Europe by gadoteratemeglumine (Dotarem): Cyclic structure & ionic
  • Similar clinical effectiveness; Less transmetallation with the macrocyclics


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

Positive Contrast

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


Pre Contrast

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.

Post Contrast

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.



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.

Negative Contrast


USPIO Assessment of Atherosclerotic Plaques

SPIO are Useful For Identifying Hepatic Tumors

Before Targeting

After Targeting

Pre Contrast

Post Contrast

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)

20-30 nm


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

Cardiovascular imaging

High Detection Sensitivity 0.7 x0.7mm

High Contrast and Resolution 0.1 x0.1mm

Canine External Jugular Vein

Human CEA specimen (2h)

Increasing Payload

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.


unique quantitative mri signatures unstable plaque imaging with 19 f mri

[NP] (nM)





Unique, Quantitative MRI Signatures “Unstable” Plaque imaging with 19F MRI

Optical Image

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

Cancer MR


Winter et al Cancer Res. 63,5838-5843

Winter et al FASEB Journal. 2008;22:2758-2767.