The images are obtained by mapping the distribution of an administered radiopharmaceutical within the body. The radiation is emitted from within the patient and subsequently detected in the imaging device, unlike transmitted through the patient from an external X-ray source (CTs and radiographs). The specific organ function depicted is determined by the biological behavior of the radiopharmaceutical. Conventional imaging with the use of a gamma camera is referred to as planar imaging. More recently, the single photon emission computed tomography (SPECT) has been developed which produces axial slice imaging through the body. SPECT uses a gamma camera to record images at a series of angles around the patient, and the resultant data can be processed using filtered back projection and iterative reconstruction algorithms. SPECT gamma cameras can have one, two, or three camera heads. The more advanced imaging is positron emission tomography (PET) that is also an axial projection acquisition-based technique. PET exploits the positron annihilation process where two 0.51 MeV back-to-back gamma rays are produced. If these gamma rays are detected, their origin will lie on a line joining two of the detectors of the ring of detectors which encircles the patient.

It took more than 40 years for the PET to reach its current state as a clinically useful tool. It is primarily due to the challenge in engineering the electronic components of medical imaging instrument to be merged into the contemporary imaging modality. The major breakthrough in positron imaging heralded with the development of positron camera in 1960 which produce planar images [1]. Later the same year, true transaxial positron tomography utilizing a ring system of detectors was produced by Brookhaven National Laboratory group.

With the advent of advanced reconstruction techniques accompanying CT, the PET scanning took a giant leap ahead. The prototype of modern day positron emission computed tomography was first implemented by Phelps and colleagues in the mid-1970s [2].

More recently, the limited anatomical definition of radionuclide imaging has been addressed to some degree by the development of hybrid imaging techniques in which radionuclide imaging devices are combined with computed tomography in a single imaging system [3]. The resulting images display the functional data obtained from the radionuclide distribution (in color), overlaid on the anatomical information from CT (in gray scale) [3]. As the two image data sets are acquired almost simultaneously using the same imaging device, the two data sets can be co-registered very accurately. Not only do these hybrid systems allow abnormalities seen on radionuclide images to be assigned to precise anatomical structures, but they also enable the morphological appearances of disease processes depicted by CT to be assimilated into the interpretation of the findings on radionuclide images. For example, such combined interpretation can aid the distinction of malignant and inflammatory causes of uptake of the positron-emitting radiopharmaceutical ¹⁸F-fluorodeoxyglucose (FDG) [4]. Further advantages of hybrid systems include the use of the CT data to correct radionuclide images for artifacts resulting from attenuation of photons travelling through the body and the ability to incorporate radionuclide image data into CT-based radiotherapy planning systems.

The radioactivity is generally administered to the patient in the form of a radiopharmaceutical agent or radiotracer. This follows some physiological pathway to accumulate for a short period of time in some specific organ of the body (Table 14.2). A good example is ^99mTc-tin colloid which following intravenous injection accumulates mainly in the liver. The substance emits gamma rays, and we can produce an image of its distribution using a nuclear medicine imaging system. This image can tell us the physiological functional information of the liver or localize the diseased sections.

Nuclear medicine procedures are best served by tracers labeled with a radionuclide that has a physical half-life that is long enough to allow for imaging in a reasonable amount of time, but not so long as to continue to irradiate the patient much beyond that imaging. Thus, radiotracers cannot be stored but must be generated daily for immediate use. To provide for tracers labeled with short-lived radionuclides, generators containing the parent material are constructed to provide an extended source of the daughter; alternatively, the radionuclide may be generated in a medical cyclotron, used to label a tracer, and the tracer shipped to the nuclear medicine department for use. This latter method is generally employed for positron-emitting radionuclides, the exception being rubidium-82, a blood flow PET tracer produced in a generator. The most commonly used radionuclide in nuclear medicine procedures is Tc-99m, and the generation of this radionuclide is from molybdenum-99 (Mo-99)-Tc-99m generator. Discussion on moly-generator is beyond the scope of this book.

Other widely used radionuclide tracers which need to be discussed in detail are the PET radionuclides. The most commonly used radionuclides for PET include fluorine-18 (F-18), carbon-11 (C-11), nitrogen-13 (N-13), and oxygen-15 (O-15). In fact, the successful synthesis of F-18 and the application of 18F-FDG had provided another major drive for the advancement of PET [5, 6].

FDG is the most commonly used tracer for PET but is plagued with false-positivity. For instance, the overall accuracy of FDG-PET in detecting a solitary pulmonary nodule is in the order of 90 %, but false positivity due to granulomatous diseases like tuberculosis leads to incorrect diagnostic categorization due to similar uptake of FDG by affected cells. Tracers that use cellular mechanism for which tumor tissue will be different from that of normal tissue will reduce the incidence of false positivity. One such mechanism that is prominent for tumor tissue is its high cellular proliferation. Tracer targeting this cellular feature will provide an appropriate diagnostic categorization of tumor tissue. F-18 fluoro-deoxy-L-thymidine (FLT) is a promising candidate which gets incorporated in the DNA in a fashion similar to that of natural thymidine in the cell nucleus. The cellular proliferation is earmarked by mitosis which leads to DNA synthesis and hence specific increased uptake of FLT which can be imaged using FLT-PET. On the downside, organs like the liver and bone marrow have high affinity for FLT even under normal conditions due to high cellular turnover. Hence, FLT is of less use in detecting primary or metastatic lesion in these sites.

The success of nuclear medicine applications depends on the detection of signals emitted by an injected radionuclide that is concentrated in the pathological tissue under evaluation. For the radionuclide to concentrate in the specific target tissue, it should be tagged to a modified biomolecule for which the cells at the target location have high affinity for specific uptake. The substitution of radionuclide onto the biomolecules will not significantly alter the reaction time or mechanism of the molecule; hence it is taken up as if it is the natural substrate for the cell.

The common cellular mechanisms that are the targets for tracing the specific uptake of radionuclides are:

Radiation exposure is a very critical issue which needs to be addressed in all radionuclide studies. If radiation exposure exceeds the permissible limit, it will have effects that may range from trivial to fatal with short-term and long-term sequela-like radiation sickness, vomiting, alopecia, radiation enteritis, GI bleeding, radiation burns, skin carcinoma. On an average, each individual is exposed to a natural background radiation of 3 mSv annually from naturally occurring radioactive materials and cosmic rays from outer space while the largest source of background radiation comes from radon gas. The maximum permissible dose (MPD) per year is for:

370 MBq of 18F-FDG delivers a dose of 11 mSv to a patient. A patient who has undergone a therapeutic procedure with sealed or unsealed radionuclides may deliver a high radiation dose to people coming in contact with him/her. Hence, a guidance level of 1,000 MBq has been laid as a standard for discharge of patients who had recently undergone radionuclide therapy.

See Table 14.3 for the diagnostic CT effective radiation doses. See Table 14.4 for effective radiation doses for various radionuclide studies.

Knowledge and compliance with the good clinical practice (GCP) is essential for everyone involved in clinical research trials for nuclear medicine. Clinical trials should be carried out within the framework of a good clinical practice environment in accordance with international guidelines and regulations as detailed in the Declaration of Helsinki [11, 12]. The International Commission of Radiological Protection and the World Health Organization (WHO) have publications that deal with this issue in clinical research. While GCP should form the backbone to successful nuclear medicine clinical studies, radiopharmaceuticals used in these trials need to be produced according to the good manufacturing practice (GMP) [13].

Radiopharmaceuticals for clinical research purposes must be manufactured in accordance with the basic principles of GMP. Due to their short half-lives, many radiopharmaceuticals are administered to patients shortly after their production, so some elements of the quality control may be retrospective. Therefore, strict adherence to GMP is essential. Special attention should be given to the production area environment and personnel, the two basic requirements of GMP production.

Since lots of confounding parameters exist in nuclear medicine, it is a good practice to stick to certain established standards laid by the regulatory bodies, advisory committee, professional organization, and manufacturer’s guidelines to ensure quality control of the imaging equipment, radiopharmaceutical tracers, procedure, and imaging protocol. Quality control starts at the time of installation and continues throughout the life cycle of the equipment. It is an ongoing process involving measurements and analyses designed to ensure that the performance of a procedure or instrument is within a predefined acceptable range and to keep it operating at peak performance all the time [14]. Therefore, it is a critical component of routine nuclear medicine practice. A detailed explanation on the quality control program is beyond the scope of this book.

The common quality control measures followed routinely in nuclear medicine practice are:

Positron emission tomography (PET) is an imaging technique based on nuclear physics principles that provides in vivo measurements in absolute units of a radioactive tracer. One of the attractive aspects of PET is that the radioactive tracer can be labeled with short-lived radioisotopes of the natural elements of the biochemical constituents of the body (¹⁸F-fluoro-2-deoxy-glucose or [¹⁸F]-FDG). This provides PET with a unique ability to detect and quantify physiologic and receptor processes in the body, particularly in cancer cells, which is not possible by any other imaging techniques today. Oncologic PET studies now represent almost 90 % of all clinical studies performed in clinical PET centers worldwide [15–19].

Although ¹⁸F-FDG is the most commonly used positron-emitting tracer in PET imaging, there are measurement of tissue blood flow, oxygen metabolism, glucose metabolism, amino acid and protein synthesis and nucleic acid metabolism that have all been demonstrated in PET oncology clinical studies using other tracers [20–23]. Labeling of a large array of other compounds including hypoxic markers, amino acids, DNA proliferation markers, and chemotherapy drugs with ¹¹C and ¹⁸F has been studied in various clinical trials (Table 14.5) [17, 22, 23].

The practical and ethical issues associated with PET examination poses difficulty in the conduct of randomized controlled trials; thus, the establishment of diagnostic accuracy and impact on patient management are mainly obtained from clinical practice [18, 24]. There is increasing evidence for the role of PET in staging, monitoring treatment response and biologic characterization of tumors [15–19, 21–23, 25–30].