Lecture 21 BIOE 498/598 DP 04/16/2014

1. Lecture 21BIOE 498/598 DP04/16/2014

2. 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) Tools that enable visualization and quantification in space and over time of signals from molecular imaging agents MRI

3. Characteristics of some Clinically Relevant Imaging Modalities Low sensitivity Short-lived radioisotopes Ca interference Slow Poor depth penetration www.scielo.br/.../bjp/v36n1a/a05tab01.gif

4. NMR  MRI: 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 Bloch Purcell Ogawa

5. 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. 

6. 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)

7. 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.

8. 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).

9. 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.

10. 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.

11. 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.

12. 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.

13. 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

14. 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

15. 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)

16. 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.

17. 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.

18. Rule of Thumb! • T1 relaxivity Bright signal • T2 relaxivity Dark signal

19. MR Manipulation of Inherent Tissue Contrast Importance of Exogenous Contrast T1-weighted T2-weighted 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 Tissue T1 (ms) T2 (ms) Native Tissue Contrast Can Be Altered Pharmacologically Grey Matter (GM) 950 100 White Matter (WM) 600 80 Muscle 900 50 Cerebrospinal Fluid 4500 2200 Fat 250 60 Blood 1200 100-200

20. 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.

21. Concept of Magnetism Ferromagnetic

22. 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. M

23. Equipments Needed 3T magnet RF Coil gradient coil (inside) Magnet Gradient Coil RF Coil Source: Joe Gati, photos

24. 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 http://strangeworldofmystery.blogspot.com/2008/12/does-earths-magnetic-field-leaking.html

25. Safety Things fly! Anyone entering the magnet must be metal free

26. Advantages • Excellent anatomical detail especially of soft tissues. • Visualizes blood vessels without contrast: magnetic resonance angiography (MRA). • Intravenous contrast utilized much less frequently than CT. Disadvantages • High operating costs. • Poor images of lung fields. • Inability to show calcification with accuracy. • Slow

27. T1 Contrast Agents

28. 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 Gd-BOPTA 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

29. 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

30. Gadomer-17: A Dendritic Contrast Agent Gadofluorine Micellar Blood Pool Contrast Agent Dendritic 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. Micelles

31. T2 Contrast Agents

32. 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

33. 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

34. Colloidal Iron Oxide Nanoparticle (CION) 20-30 nm Fe3O4 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

35. In vitro and ex-vivo Targeted MRI with CION with anti-Fibrin Antibody CION Control Fibrin-rich Plasma Clots CION CION Rapid T1w Imaging Senpan, Caruthers, Pan, Wickline, Lanza, 2009 ACS Nano

36. 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. “HOT SPOT” MRI

37. [NP] (nM) >1.5 1.0 0.5 0 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.

38. 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 Imaging Winter et al Cancer Res. 63,5838-5843 Winter et al FASEB Journal. 2008;22:2758-2767.