Radiopharmaceuticals for PET and SPECT Imaging: A Literature Review over the Last Decade

Radiopharmaceuticals for PET and SPECT Imaging: A Literature Review over the Last Decade

Abstract: Positron emission tomography uses radioactive tracers and enables the functional imaging of several metabolic processes, blood flow measurements, regional chemical composition, and/or chemical absorption. Depending on the targeted processes within the living organism, different tracers are used for various medical conditions, such as cancer, particular brain pathologies, cardiac events, and bone lesions, where the most commonly used tracers are radiolabeled with fluorine eighteen. Oxygen fifteen isotope is mostly involved in blood flow measurements, whereas a wide array of carbon eleven-based compounds have also been developed for neuronal disorders according to the affected neuroreceptors, prostate cancer, and lung carcinomas. In contrast, the single-photon emission computed tomography technique uses gamma-emitting radioisotopes and can be used to diagnose strokes, seizures, bone illnesses, and infections by gauging the blood flow and radio distribution within tissues and organs. The radioisotopes typically used in SPECT imaging are iodine one twenty-three, technetium ninety-nine m, xenon one hundred thirty-three, thallium two hundred one, and indium one hundred eleven. This systematic review article aims to clarify and disseminate the available scientific literature focused on PET/SPECT radiotracers and to provide an overview of the conducted research within the past decade, with an additional focus on the novel radiopharmaceuticals developed for medical imaging.

One. Introduction

Over the last decade, the initial focus on medical imaging based on detection and diagnosis has reoriented towards prognosis, tissue characterization, and prediction of treatment efficacy. To this extent, functional imaging, such as positron emission tomography and single-photon emission computed tomography, has become essential in the clinical decision-making process in various fields of medicine. Moreover, hybrid imaging, combining SPECT and PET with computed tomography or magnetic resonance imaging, has increased the diagnostic accuracy of both PET and SPECT by the benefit of the morphological information obtained by the CT and MRI scans and the implementation of attenuation correction. PET represents a quantitative imaging tool that appears to surpass the SPECT technique. However, the answer to the highly debated question of which modality will monopolize the nuclear imaging technologies remains unsettled. Traditionally, when compared with SPECT, PET technology provides better image resolution, less attenuation (due to higher photon energy) and scatter artifacts, and,

consequently, superior diagnostic capabilities. Two of the most important advantages of PET over the SPECT modality are represented by PET's higher sensitivity and more robust and flexible tracers, making PET a versatile and tool for clinical and research applications. These advantages, however, come with a high cost burden that limits the availability of PET imaging. Most positron-emitting radioisotopes have short half-lives and require in-house cyclotron production. Therein lies the main advantage of SPECT. Radiopharmaceuticals used for SPECT imaging are cheaper and easy to distribute, and in particular conditions, they present more specific targeting abilities of the biologically active molecules due to the longer half-life of single-photon emitters, allowing for an accurate description of the biological processes at equilibrium in vivo. It is worth noting that the development of the radiopharmaceutical compounds related to distinctive diagnostic and therapeutic targets, and therefore used in both imaging modalities, goes hand in hand with the acquisition systems' development.

Figure one shows the number of scientific publications over the last ten years related to radiotracers for PET/CT and SPECT/CT techniques. A clearly increasing trend of publications is observed for both cases, yet with a number of SPECT papers, on average, about seven times smaller.

PET represents the functional imaging technique widely used nowadays for clinical diagnosis of a large variety of diseases, and employs short half-life positron-emitting isotopes, such as carbon eleven and fluorine eighteen, for in vivo measurement of biological processes. The technique is also heavily used as a research tool in preclinical studies using animals and for the detection of specific molecules within the human body. In the nineteen sixties, radiopharmaceuticals were already attributed as drugs designed for in vivo diagnosis and treatment applications. A radiopharmaceutical compound consists of: one. a molecular structure identified as a vehicle molecule and two. a positron-emitting radionuclide. The radioisotope is attached to the vehicle molecule, also known as ligand, and then injected into the body as a radioactive tracer.

Commonly, the vehicle molecules are responsible for the chemical and biochemical reactions within the body; therefore, the connections between vehicle structures and radionuclides are stabilized using chemical linkers. The ligands must present high selectivity and specificity towards their targets. These target sites can be either transporters, enzymes, selected receptors, or antigens. Moreover, the targets can be part of metabolic alterations, tissue hypo-oxygenation, or changes in gene and/or protein expression. However, in pathological conditions, the target's function might be significantly altered, further affecting the biological interactions between the vehicle part and its target, particularly in tumors, where the receptors, transporters, and enzymes' expression pathways are heavily affected.

The PET technique is based on the detection of emitted radioactivity levels of the tracer, normally administrated through an intravenous injection. The radiation doses are comparable to those used in computed tomography scans. The measurement of glucose consumption rates within different parts of the body is the most common use of PET imaging based on the accumulation of the radiolabeled glucose analogue eighteen-fluorodeoxyglucose. Considering that glucose metabolizes at faster rates in malignant tumors when compared with benign ones, this technique is widely used for whole-body scans in order to stage the cancer. Further applications of PET scans include blood flow and oxygen consumption in the brain; tracking of specific neurotransmitters, such as dopamine in Parkinson's disease; or, in cardiology, evaluation of myocardial viability.

A PET radionuclide selection should be considered based on several crucial aspects regarding, first of all, the radionuclide availability, then its physical characteristics, and its radiochemical and radiopharmacological issues. With respect to radiochemical considerations, since their primary chemical form is not predisposed to direct labeling reactions, an initial activation step is required for reactive chemical modifications.

A wide array of PET radiopharmaceuticals have been tested and evaluated in clinical trials, targeting a large spectrum of diseases. While all these PET compounds present different compositions in terms of their vehicle molecules (or ligands), they all must follow the same requirements-as imaging agents-with high specificity, high binding affinity, low toxicity, stability (e.g., against different enzymes in plasma), rapid clearance from nontargeted tissue, accessibility at low costs, and permission for clinical usage. The selection or development of a radiopharmaceutical has to meet certain criteria in order to be adequate for an exact biological targeting or disease. Specifically, the radionuclide must have a reasonable half-life, depending on the desired use. In addition, characteristics such as size or charge of the molecule, its specific activity, lipophilicity, stability, and the metabolism of the radiolabeled compounds are directly correlated to the specificity of each biological target. Thus, through quality control tests, aspects concerning the physicochemical, radiochemical, or biological properties are also required.

As previously mentioned, alongside the half-life of the radionuclide, the size and mass also play an important role in eliminating the radiopharmaceutical out of the in vivo system. The size of the molecule ensures a better clearance from circulation and has an impact over the in vivo distribution patterns of the radiopharmaceutical. For instance, larger molecules have longer localization time when compared with small molecules, and they cannot be filtered by the kidneys. Additionally, the charges also influence their solubility in different solvents. Noncharged molecules are prone to be more soluble in lipids and organic solvents, whereas radiopharmaceuticals with greater charges present better solubility in aqueous solution.

The radiolabeled compound preparation should be considered in an aqueous solution with a pH as close as possible to the pH of blood. In addition, the ionic strength and osmolality should also be compatible with blood. Their solubility is influenced by their sizes, masses, charges, shapes, and a fundamental physicochemical property, their lipophilicity. Last but not least, lipophilicity has a significant impact on the absorption, distribution, and elimination of drug molecules. For example, neutral lipophilic molecules are usually the only ones able to penetrate the blood-brain barrier.

Almost all drugs are able, to a certain extent, to bind to blood components. Protein binding depends on the nature of the protein, the concentration of the anions, the charge of the radiopharmaceutical compound, and the pH. Increased lipophilicity encourages nonspecific binding to albumin and other plasma proteins. Metals have a high affinity for proteins, and that leads to a high possibility of ion exchange between a metal complex and a protein. Therefore, the protein binding properties should also be thoroughly studied before clinical use.

In terms of stability, the physicochemical parameters, such as temperature, pH, and light, must be carefully established for the radiopharmaceutical preparation and storage. With regard to the compound's metabolism, if the radiopharmaceutical compound can be metabolically decomposed, its biodistribution becomes affected because of the mixture of the intact agents and metabolic fragments from the decomposed radiolabeled molecule.

The blood metabolism might also alter the delivery of the radiopharmaceutical to the target site. Moreover, the metabolic compounds might get stuck at the target site, and therefore, the relative concentration of the intact radiolabeled molecules, as well as the relative concentration of the metabolic products, must be carefully measured in order to obtain meaningful results.

Finally, depending on the concentration of target molecules, a radiopharmaceutical compound must exhibit a proper specific activity. Specific activity is a measure of the number of radioactive probe molecules that are bound to the targeted system. Possible ways of increasing the specific activity include the purification of the radiopharmaceutical after radiolabeling or the reduction of the quantity of precursor for radiolabeling.

On the other hand, SPECT and planar scintigraphy account for almost eighty percent of all nuclear medicine scans performed worldwide. SPECT radiopharmaceuticals have similar design considerations as described for PET but are based on gamma-emitting radioisotopes, such as ninety-nine m Tc, one twenty-three I, one thirty-one I, one eleven In, sixty-seven Ga, two hundred one Tl, eighty-one m Kr, one thirty-three Xe. While PET has the advantage of higher resolution and sensitivity, SPECT is more accessible and cheaper. PET/CT hybrid imaging accounted for the main limitation of PET, namely, uptake localization. With the adoption of PET/CT imaging in clinical practice, focus has shifted to developing novel PET radiopharmaceuticals. However, as mentioned in recent reviews, SPECT still plays an important role in nuclear medicine imaging. A wide variety of radiopharmaceuticals are available for SPECT imaging techniques that are integrated into the clinical decision-making process, such as ninety-nine m Tc-sestamibi and ninety-nine m Tc-tetrofosmin for the diagnosis of cardiac ischemia or ninety-nine m Tc-labeled diphosphonates for identifying bone metastasis in breast or prostate cancer.

In recent years, developments in SPECT imaging systems based on new solid-state cadmium telluride and zinc telluride crystals and collimator design led to an increase in resolution and sensitivity. Furthermore, advances in radiometal-based radiopharmaceuticals for PET, specifically the successful development of sixty-eight Ga-PSMA-eleven, can be translated to SPECT radiometals, such as technetium. These considerations have rekindled interest in designing novel SPECT radiopharmaceuticals.

As with all medical applications that use ionizing radiation, the benefit of PET and SPECT procedures must be evaluated considering the risks to patient. Dose optimization takes into consideration the administration of the amount of radioactivity that provides images of sufficient quality so as to achieve the relevant clinical information while maintaining the lowest possible radiation dose to the patient. There are different aspects that must be taken into account when deciding the administered dose, such as individual patient physiology and anatomy or the design of the imaging equipment used for the procedure. Average effective doses for nuclear medicine procedures range from zero point three to twenty millisieverts with SPECT having generally lower effective doses than PET mainly due to the physical characteristics of the radioisotopes used. For example, the average effective dose for a ninety-nine m Tc-one-sestamibi cardiac rest-stress test (two-day protocol) with an administered activity of one thousand five hundred megabecquerels is twelve point eight millisieverts, while for a cardiac eighteen F-FDG PET scan with an administered activity of seven hundred forty megabecquerels, the average effective dose is fourteen point one millisieverts. Hybrid systems increase the radiation exposure by the addition of a CT scan. The additional radiation dose depends on whether the CT scan is used for attenuation correction, localization, or diagnostic acquisitions.

The present review paper provides an overview of current and novel PET and SPECT radiopharmaceuticals used in the past ten years for medical and preclinical applications. The article comprises PET and SPECT radiotracers used in clinical and preclinical oncology for central nervous system imaging, cardiovascular events, bacteria imaging, inflammation and infections, and nonspecific interactions. Imaging using PET and SPECT agents for other diseases were also considered.