A radioligand is a microscopic particle which consists of a therapeutic radioactive isotope and the cell-targeting compound — the ligand. The ligand is the target binding site; it may be on the surface of the targeted cancer cell for therapeutic purposes. Radioisotopes can occur naturally or be synthesized and produced in a cyclotron/nuclear reactor. Types of radioisotopes include Y-90, H-3, C-11, Lu-177, Ac-225, Ra-223, In-111, I-131, and I-125. Thus, radioligands must be produced in special nuclear reactors for the radioisotope to remain stable. Radioligands can be used to analyze/characterize receptors, to perform binding assays, to help in diagnostic imaging, and to provide targeted cancer therapy. Radiation is a novel method of treating cancer and is effective in short distances along with being unique/personalizable and causing minimal harm to normal surrounding cells. Furthermore, radioligand binding can provide information about receptor-ligand interactions in vitro and in vivo. Choosing the right radioligand for the desired application is important. The radioligand must be radiochemically pure, stable, and demonstrate a high degree of selectivity, and high affinity for their target.
History
Wilhelm Roentgen is credited with the discovery of radioactivity in 1895 with many others such as Antoine Henri Becquerel, Pierre Curie, and Marie Curie following closely behind to further advance the field of radioactivity. John Lawrence, a physicist at The University of California Berkeley, first used nuclear medicine in humans came in 1936 after extensive use of radioactive phosphorus in mouse models. Often called the father of nuclear medicine, Lawrence treated a leukemia patient with radiophosphorus, which was the first time a radioactive isotope has been used to treat human patients. Another pioneer in the field, Sam Seidlin, in partnership with Saul Hertz, treated a case of thyroid cancer with radioactive iodine (I-131) 1946. In the 1950s, nuclear medicine began to gain traction as a medical specialty with the Society of Nuclear Medicine forming in 1954 and later releasing the first copy of the Journal of Nuclear Medicine in 1960. The use of radioligands and nuclear tagging started to gain popularity in the early 1960s when Elwood Jensen and Herbert Jacobsen (1962) and later Jack Gorski, David Toft, G, Shymala, Donald Smith, and Angelo Notides (1968) attempted to identify the estrogen receptor. The American Medical Association (AMA) officially recognized Nuclear Medicine as a medical specialty in 1970 and the American Board of Nuclear Medicine was established in 1972. Progress came quickly in 1973 when Edward Hoffman, Michael M. Ter-Pogossian, and Michael E. Phelps invented the first PET camera for human use. The 1980s brought early radioligand studies for neuroendocrine tumors (NETs) which continued into the early 2000s. In 2017 the European Union (EU) approved the use of radioligand therapy for NETs with the U.S. following close behind in 2018.
Radioactive isotopes commonly used
Radioisotope Half-life Ray emission UsesIodine-12560 daysgamma raysIodine-125 is used in nuclear medicine for biological assays, as iso seeds for localized prostate cancer, and as internal radiation brachytherapy for cancers.Iodine-12313 hrsgamma raysIodine-123 is preferred for diagnostics and imaging, especially for the thyroid, as it has a short half-life (13 hrs) and can clearly show the thyroid's uptake of iodine with lower radiation energy than I-131.Iodine-1318 daysbeta particles gamma raysIodine-131 is used as a part, along with a urea based ligand MIP-1095 that binds specifically to the prostate membrane, of a radioligand therapy in clinical trials for metastatic prostate cancer.Fluorine-18109.7 minutesbeta positive decay (positron emission)Fluorine-18 is used in PET imaging and radioligand diagnostics for the early detection of disease. Furthermore, since F-18 is a small lipophilic molecule, it can readily cross the blood brain barrier and be used in diagnostic imaging of glucose metabolism in the brain.Flortaucipir F-18 Because it can bind to PET imaging ligands, it is used for detecting amyloid aggregation which indicates progression of Alzhiemer's disease in brain tissue.Iridium-19274 daysgamma raysThe most common uses of Iridium-192 are: cervical cancer, head, and neck cancer, and prostate cancer. Ir-192 can also be used in the radionuclide therapy called high-dose rate brachytherapy.Xenon-1335.2 daysbeta and gamma emissionsXe-133 is an inert gas that, along with CO2, can be inhaled to provide diagnostic information on the lung in adults and neonates using SPECT or nuclear imaging.Yttrium-9064 hourspure beta emitterYtrium-90 can be used for internal radiation therapy to diagnose liver metastases. Y-90 emits the highest amount of beta radiation energy and can be used as radioligand therapy for B-cell non-Hodgkin Lymphoma or pancreatic cancer.Carbon-1120 minutespositron emissionCarbon-11 can be used to find neuroinflammation through PET imaging of a specific translocator protein that indicates neuroinflammation if found. C-11 can also be used for PET radioligand imaging of serotonin transporters in the primate/pig brain cortical regions. C-11 is also very unstable and decays into stable Boron-11.Indium-11167 hoursgamma radiation (low-energy)Indium-111 is unstable and decays by electron capture to a stable cadmium-111. It can be used for planar SPECT imaging for diagnostic purposes and diagnostic imaging of the presence of somatostatin receptors on various neuroendocrine tumors.Tritium (Hydrogen-3) (H-3)12 yearsbeta radiationHydrogen-3 is used for in vitro radioligand binding analysis of brain tissue and competition/saturation radioligand binding assays.Strontium-89 (Sr-89)50.5 daysbeta radiationStrontium-89 is used as a radioligand therapy for bone cancers to relieve bone pain as Sr-89 is easily absorbed in osseous tissue.Strontium chloride SR 89 (Intravenous route, injection route) description and brand names - Mayo Clinic. (2024, February 11). Top-ranked Hospital in the Nation - Mayo Clinic. Lutetium-1776.6 daysimageable gamma photons beta particlesLutetium-177 is utilized for advanced metastatic prostate cancer or B-cell non-Hodgkin's lymphoma.Radium-22311.4 daysalpha particlesRadium-223 is a calcimimetic specifically used for advanced metastatic prostate cancer or B-cell non-Hodgkin's lymphoma.
Ligands
A ligand is a molecule utilized for cell-signaling that binds to a target tissue for cellular communication. There are many different types of ligands, including internal receptors, cell surface receptors, ion channel receptors, G protein-coupled receptors (GPCRs), and enzyme-linked receptors. Ligands can be divided into two categories, agonists or antagonists. Agonists behave similarly to natural ligands, while antagonists are inhibitors and block the binding of the natural ligand. There are many different subtypes of agonists, including endogenous agonists, super agonist, full agonist, inverse agonist, and irreversible agonist.
Radioligands are made up of the radioisotope, linker, and ligand. This structure allows the compound to identify and bind to the target tissue while retaining the ability to be tracked and imaged clinically. When a radioligand binds to its target, it alters the microenvironment of the receptor and surrounding tissue, partially due to the structure of the radioligand itself. Without both the high affinity ligand and the radioisotope, the efficiency of this process is lost.
Use in drug delivery and release Radioligands are administered through four main routes: intravenously, subcutaneous injection, intraperitoneally, and orally. While intravenous application is the most used route of injection, the route is dependent on the mechanism of action and overall aim of the binding. Before application of the ligand, clinicians will perform imaging, generally via positron emission tomography (PET) or single-photon emission computed tomography (SPECT) for baseline comparison after radioligand administration. Once the radioligand is administered, the radioligand will travel to the target tissue and selectively bind. The structure of the compound allows clinicians to easily identify the path traveled and the destination via repeated imaging and the signal put out by the radiotracer attached to the ligand.
Direct radiotherapy performed via ionizing radiation can cause tissue damage and hypoxia to tissues other than the target. While this effect is lessened in a target radiotracer therapy utilizing radioligands, there is still an impact on the surrounding tissue described as Radiation Induced Bystander Effect (RIBE). Surrounding cells altered by the radioligand and displaying RIBE can show signs of stress, chromosomal abnormalities, or even experience cell death. However, the type of radiation used, whether 𝜶, β, or both can have a dramatically different effect on both the target binding site and surrounding tissue. Changes in nearby tissue is not the only possible impact of ligand therapy, there may be immunologic responses from the target tissue that cause changes remotely. This has been dubbed the "abscopal effect". While this mechanism is not well understood, it explains the impact of other tissue, both benign and malignant, after targeted radiotherapy.
Use in imaging Imaging is a useful tool in visualization of the radioligand after injection, with positron emission tomography (PET) and single-photon emission computed tomography (SPECT) being the most common types of imaging. PET scans are often utilized after radioligand administration because of the ease of use, image accuracy, and non-invasive nature. While PET and SPECT scans function similarly when imaging radioligands, the main difference lies in the type of radiation used, with PET scans utilizing positrons and SPECT utilizing gamma rays. When comparing the two modalities, PET offers much better image quality and high diagnostic proficiency, however, the high cost and the short half-lives of the positron-emitting isotopes limit their overall availability. Alternatively, SPECT imaging is more dynamic because of the lower cost burden and longer half-lives of single-photon emitters. With advances in technology came hybrid imaging that can combine PET, SPECT, computed tomography (CT), and magnetic resonance imaging (MRI). Some hybrid imaging modalities include: PET–CT, SPECT/CT, and PET/MRI. Although combined imaging presents both cost and availability barriers, the technology is an extremely useful diagnostic tool. Often, the patient does not have to be moved for both imaging types to be completed, and the clinicians are provided with rich, multi-dimensional imaging.
Binding assays Measuring the extent and kinetics of radioligand binding is important in determining information about binding sites of radioligands, and subsequent affinity to potential drugs. Three different binding assays are typically used for radioligand binding: saturation, competition, and kinetic binding.
Saturation binding Saturation binding measures the specific binding of a radioligand at varying concentrations while at equilibrium. Through this method, the number of receptors can be determined as well as affinity of the ligand to these receptors. Saturation binding experiments are often called "Scatchard experiments" as they can be graphed as a Scatchard plot.Mailman, R., & Boyer, J. (1997, July 31). Theory and Practice of Receptor Characterization and Drug Analysis (a review of Theory and Practice of Receptor Characterization and Drug Analysis, UNC School of Medicine).
Competition binding