Introduction to Different PET Radiopharmaceuticals and Hybrid Modalities (PET/CT and PET/MRI)

Abstract

Positron Emission Tomography (PET) is an imaging technique performed by using positron emitting radiotracers. Positron decay occurs with neutron-poor radionuclides and consists in the conversion of a proton into a neutron with the simultaneous emission of a positron (β+) and a neutrino (ν). The positron has a very short lifetime, and after the annihilation with an electron simultaneously produces two high-energy photons (E = 511 keV) in approximately opposite directions that are detected by an imaging camera. The PET scanning is based on the so-called annihilation coincidence detection (ACD) of the 511 keV γ-rays after the annihilation. Tomographic images are formed collecting data from many angles around the patient by scintillating crystals optically coupled to a photon detectors used to localize the position of the interaction and the amount of absorbed energy in the crystals (Table 1.1) [1].

1 Physical Principles of Positron Emission Tomography and Hybrid Modalities

Positron Emission Tomography (PET) is an imaging technique performed by using positron emitting radiotracers. Positron decay occurs with neutron-poor radionuclides and consists in the conversion of a proton into a neutron with the simultaneous emission of a positron (β+) and a neutrino (ν). The positron has a very short lifetime, and after the annihilation with an electron simultaneously produces two high-energy photons (E = 511 keV) in approximately opposite directions that are detected by an imaging camera. The PET scanning is based on the so-called annihilation coincidence detection (ACD) of the 511 keV γ-rays after the annihilation. Tomographic images are formed collecting data from many angles around the patient by scintillating crystals optically coupled to a photon detectors used to localize the position of the interaction and the amount of absorbed energy in the crystals (Table 1.1) [1].

Table 1.1 Properties of PET scintillator crystals

The key properties that characterize the PET scanner performances are the spatial resolution, the sensitivity, the Noise-Equivalent Count Rate (NECR) and the contrast [2]. The projection data acquired in the form of sinograms are affected by a number of factors that contribute to the degradation of the final images and hence to the PET scanner performances, as reported in Table 1.2.

Table 1.2 The PET scanner performance and the intrinsic PET limitations

Two classes of reconstruction techniques exist: the analytical and the iterative methods [3]. The most used analytical method is the backprojection. To compensate the blurring, a filter is applied to the projections before they are back-projected onto the image [i.e. filtered backprojection (FBP)]. In modern scanners, the image reconstruction algorithms are based on iterative methods, which approach the true image by means of successive estimations, in order to converge to an image that best represents the original object. These algorithms are known as expectation maximization (EM) and Ordered Subset Expectation Maximization (OSEM) algorithm [4].

2 Hybrid Scanners: PET/CT and PET/MRI

Combined PET/CT systems were commercially available from 2001 and in a very short time the dedicated PET scanner was completely replaced by hybrid PET/CT. The ability of hybrid PET/CT systems to accurately identify the anatomic location of diseases and to provide attenuation-corrected images are the main causes of their rapid success and diffusion [5]. Modern clinical PET/CT consists in a high-performance PET scanner in-line with a high-performance CT scanner arranged in sequential gantries. The scanner table moves along the gantry axis in order to subsequently acquire CT and then PET data. A software integrated in the system has to check if the patient bed undergoes some deflections during the translation [6]. Images of tissue attenuation from the CT scan are used to derive the PET attenuation correction factors. The latter depends on the energy of the photons: since CT X-rays and PET γ-rays have an energy of 70 keV and 511 keV, respectively, the attenuation correction factor obtained from CT must be scaled to the 511 keV photons applying a scaling factor defined by the ratio of the μ of the 511 keV photons to that of the 70 keV X-rays in a given tissue [1].

PET/MRI is a multi-modality technology combining the functional information of PET with the soft-tissue contrast of MRI. Actually, two approaches are implemented in the commercial PET/MRI scanners: sequential PET/MRI [7,8,9]. The characteristics of the three commercial PET/MRI scanners are summarized in Table 1.3.

Table 1.3 The characteristics of the three commercially available PET/MRI scanners

3 Positron Emission Tomography Radiopharmaceuticals

Radiopharmaceuticals are radiolabelled molecules consisting in a molecular structure and a radioactive nuclide. The first one defines the pharmacokinetics and dynamics within the organism, while the latter is responsible for a detectable signal and for the consequent image visualization [10]. To maintain the stability of these two components, a linker may be necessary. The most important PET nuclides and their physical characteristics are summarized below:

• Carbon-11 (¹¹C) has a physical half-life of about 20 min and decays by β⁺ emission (99.75%) and by electron capture (0.25%) to the ground state of the stable nuclide Boron-11 (¹¹B). β⁺ average energy is 386 keV, corresponding to a mean range in water of 1.3 mm. ¹¹C can be produced by different nuclear reactions; however, the main production mode is targeting Nitrogen-14 (¹⁴N) with cyclotron accelerated protons: ¹⁴N(p,α)¹⁴C.

• Fluorine-18 (¹⁸F) has a physical half-life of about 110 min and decays by β⁺ emission (96.86%) and electron capture (3.14%) directly to the ground state of the stable nuclide Oxygen-18 (¹⁸O). β⁺ average energy is 250 keV, corresponding to a mean range in water of 0.6 mm. ¹⁸F can be produced by different nuclear reactions; however, the main production mode is targeting Oxygen-18 with cyclotron accelerated protons: ¹⁸O(p,n)¹⁸F.

• Gallium-68 (⁶⁸Ga) has a physical half-life of about 67.8 min and decays by β⁺ emission (88.88%) and by electron capture (11.11%) into ⁶⁸Zn. β⁺ average energy is 830 keV, corresponding to a mean range in water of 3.6 mm. ¹⁸Ga can be produced by different nuclear reactions; however, the main production mode is using a Germanium-68 (⁶⁸Ge)- ⁶⁸Ga generator.

• Iodine-124 (¹²⁴I) has a physical half-life of about 4.2 days and decays by β⁺ emission (23%) and by electron capture (77%) to the excited level and the ground state of Tellurium-124 (¹²⁴Te). β⁺ average energy is 836 keV, corresponding to a mean range in water of 3.4 mm. ¹²⁴I can be produced by different nuclear reactions; however, ¹²⁴Te(p,n) reaction gives the purest form of ¹²⁴I.

• Copper-64 (⁶⁴Cu) has a physical half-life of about 12.7 h and decays by β⁻ emission (38%) to Zinc-64 (⁶⁴Zn) and by β⁺ emission (17.4%) or electron capture (44.6%) to the excited level and the ground state of Nickel-64 (⁶⁴Ni). β⁺ average energy is 278 keV, corresponding to a mean range in water of 0.7 mm. The main ⁶⁴Cu production modes are the following: ⁶³Cu(n,γ)⁶⁴Cu, ⁶⁵Cu(n,2n)⁶⁴Cu, ⁶⁴Zn(n,p)⁶⁴Cu, ⁶⁴Zn (d,2p)⁶⁴Cu.

The wide and feasible availability of positron emitters radionuclides is a prerequisite for successful application on a routine basis. Fluorine-18 and Gallium-68 are the most used in a clinical setting, so far. Due to its versatility, ¹⁸F-Fluorodeoxyglucose (FDG), namely a radiolabelled analogue of glucose, is the by far most widely used PET radiopharmaceutical worldwide. FDG is very useful to detect malignant tumours characterized by increased glucose metabolism. However, FDG remains a non-specific tracer and its uptake is also been observed in many benign conditions, such as infective and inflammatory processes. Therefore, over the last decade, there is a growing interest in researching and using new radiopharmaceuticals, such as radiolabelled amino acids, nucleoside derivatives, choline derivatives, nitroimidazole derivatives and peptides, able to carefully target specific biomarkers. These new generation radiopharmaceuticals allow the analysis of several molecular pathways in tumour biology including metabolism, proliferation, oxygen delivery and protein synthesis as well as receptor and gene expression (Tables 1.4, 1.5 and 1.6). Some examples of PET images with different radiopharmaceuticals are showed in Figs. 1.1 and 1.2.

Table 1.4 Metabolic and pure isotope PET tracers

Table 1.5 Receptor PET tracers

Table 1.6 Brain PET tracers

Fig. 1.1

Biodistribution of PET tracers: ¹⁸F-FDG (a), ¹⁸F-FCH (b), ¹⁸F-DOPA (c), ¹⁸F-Fluociclovine (d)

Fig. 1.2

Biodistribution of PET tracers: ¹⁸F-NaF (a), ⁶⁴CuCl₂ (b) ⁶⁸Ga-DOTATOC (c), ⁶⁸Ga-PSMA (d), ¹⁸F-FES (e)