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An Introduction to Molecular Imaging

Ga-Lai Law and Wing-Tak Wong

Department of Applied Biology and Chemical Technology, Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China

1.1 Introduction

The aim of this book is to introduce the concepts of different imaging techniques that are employed for diagnostics and therapy and the role that chemistry has played in their evolution. The book provides a general introduction to the area of molecular imaging, giving an account of the role of molecular design and its importance in modern-day techniques, with an in-depth introduction of some of the probes and methodologies employed. This first chapter introduces the different types of imaging modalities currently at the forefront of imaging and illustrates some basic concepts underlying these techniques. It acts as a simplified background to set the scene for the following chapters, which will discuss the chemical properties of molecules and the role they play in different imaging modalities. For the interested readers, other textbooks are referenced that will provide more detailed information regarding the different techniques reviewed.

In life everything is incessantly changing. There is constant evolution in life sciences, evolution in the way problems arise, and evolution in the way they are solved. Diagnostics and therapy are both important, but as Einstein said, "intellectuals solve problems, geniuses prevent them." The key challenge still remains to unravel the hidden knowledge within life sciences, which constantly challenges us with new diseases and mechanistic mutation of biological systems and pathways [1]. Again, as stated by Einstein, "once we accept our limits, we go beyond them."

Molecular imaging aims to detect and monitor mechanistic processes in cells, tissues, or living organisms with the use of instruments and contrast mechanisms without perturbing their living system. Ultimately, it is a field that utilises molecular building blocks to bring solutions to problems by specialised imaging techniques that have matured into a large integrated field enveloped within various branches of science (Figure 1.1) [2]. In the area of modern-day imaging where technology is at its pinnacle, molecular design still holds a dominant role in the forefront of molecular imaging.

Figure 1.1 Types of multidisciplinary fields related to molecular imaging.

In the past, developments in contrast agents, probes, and dyes have brought about an era of creativity where new techniques, materials, and designs have flourished to form a concrete foundation resulting in today's achievements in diagnosis and therapy (Figure 1.2). The construction of better chemical molecules will continue to help us develop a more comprehensive picture of learning about life science. Figure 1.3depicts a timeline in the development of the field [1-3].

Figure 1.2 Diagram showing the links in the design rationale of imaging agents.

Figure 1.3 An approximate timeline showing the development of the different imaging modalities [1-3].

1.2 What Is Positron Emission Tomography (PET)?

Positron Emission Tomography (PET) is a nuclear medicine tomographic modality and one of the most sensitive methods for quantitative measurement of physiologic processes in vivo [4]. This technique utilises positron-emitting radionuclides and requires the use of radiotracers that decay and produce two 511 keV ?-rays resulting from the annihilation of a positron and an electron. One of the most commonly used molecules is 18 F-labelled fluorodeoxyglucose (18FDG), which has radioactive fluorine and is readily taken up by tumours (Figure 1.4) [5].

Figure 1.4 18FDG, a typical contrast agent used in PET.

1.2.1 Basic Principles

In PET, a neutron-deficient isotope causes positron annihilation to produce two 511 keV ?-rays, which are simultaneously emitted when a positron from a nuclear disintegration annihilates in tissue. PET imaging, unlike MRI, ultrasound, and optical imaging, does not require any external sources for probing or excitation; instead, the source is generated from radioisotopes and emitted from but not transmitted through an object/patient, as in CT imaging [4-7]. Radionuclides are incorporated as part of a small metabolically active molecule to generate radiotracers such as 18FDG, which are then intravenously injected into patients at trace dosage for PET imaging. 18FDG is a favourable radiotracer because it is inhibited from metabolic degradation before it decays due to the fluorine at the 2' position in the molecule. Upon decay, the fluorine is converted into 18O. There is generally a short period of time before accumulation of radiotracers into the targeted organs or tissues that are being examined, so it is important for radiotracers to have a suitable half-life-some commonly used radionuclei have very short half-lives. Some common radionuclides used in PET are 11-C (half-life ~20 min), 13-N (~10 min), 15-O (~2 min) and 18-F (~110 min). These are produced by a cyclotron, whereas 82-Rb (76 s), which is used in clinical cardiac PET, is produced by a generator [8-9].

When a radioisotope undergoes positron emission decay (positive ß-decay), it emits a positron that travels through the tissue for a short distance (~ < 2 mm) whilst decelerating by the loss of its kinetic energy until it collides with an electron. This results in back-to-back annihilation of ?-ray photons, which move in opposite directions and are emitted nearly 180 degrees apart before being detected by scintillators and a photomultiplier tube. This type of coincidence is a true coincidence event; to detect this, the detectors are designed like a ring that surrounds the patient during the scanning procedure. Several parallel rings form the complete detection panel of the PET system in a cylindrical geometry (Figure 1.5).

Figure 1.5 Typical configuration of a PET scanner.

PET has relatively high sensitivity in detecting molecular species (10-11 - 10-12 M), even though not all annihilation photons are used for image reconstruction because not all coincidences are true coincidences. A coincidence event is assigned to a line of response where the two relevant detectors are joined (detectors opposite to each other); this allows for positional information to be located from the detected radiation without any physical collimators. This is known as electronic collimation. There are four types of coincidence events in PET: true, scattered, random, and multiple (Figure 1.6). Only true coincidence, which is the simultaneous detection of two emissions from a single annihilation event, is useful. No other events are detected within this coincidence time-window.

Figure 1.6 Different types of coincidence events.

Scattered coincidence occurs when one or both photons from a single event are scattered and both are detected; however, one of the photons must have undergone at least one Compton scattering event prior to detection. This type of event adds a background to the true coincidence event and causes overestimation of the isotope concentration as well as decreasing image contrast. In Compton scattering, a photon interacts with an electron in the absorber material, resulting in an increase in the kinetic energy of the electron as well as a change in direction in the photon. The energy of the photon after interaction is defined as:

where E is the energy of the incident photon, E´ is the energy of the scattered photon, m0c2 is the rest mass of the electron, and q is the scattering angle [10]. From Equation 1.1, it can be seen that fairly large deflections can occur with just a small loss of energy; for example, for 511 keV photons, a Compton scattering event results in a deflection of over 25 degrees but results in just a 10% loss in the photon energy. Random coincidence is the simultaneous detection of emission from more than one decay event. It occurs when two photons not arising from the same annihilation event are incident on the detectors within the coincidence time-window of the system. This contributes to statistical noise in data as well as overestimation of isotope concentration [8].

Multiple coincidences occur when more than two photons are detected by different detectors within the coincidence resolving time. This type of event either causes event mis-positioning or rejection because it is not possible to determine the line of response to which the event should be assigned. Coincidence events are grouped together to produce projection images called sonograms. Acquisition of PET images is not a simple process because data corrections are required for scattered, random coincidences as well as for the effects of attenuation, because the data acquired from the PET camera are given as projections. The measured projections are different from the projections assumed in image reconstruction [9]. Reconstruction of images from projections is computationally burdensome. Data reconstruction and correction are usually carried out by analytical or iterative methods. Analytical methods are simple, fast, and usually have predictable linear...