applied sciences Review A Picture of Modern Tc-99m Radiopharmaceuticals: Production, Chemistry, and Applications in Molecular Imaging Alessandra Boschi 1 , Licia Uccelli 2,3 and Petra Martini 2,4,* 1 Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Via Luigi Borsari, 46, 44121 Ferrara, Italy; [email protected] 2 Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Via Luigi Borsari, 46, 44121 Ferrara, Italy; [email protected] 3 Nuclear Medicine Unit, University Hospital, Via Aldo Moro, 8, 44124 Ferrara, Italy 4 Legnaro National Laboratories, Italian National Institute for Nuclear Physics (LNL-INFN), Viale dell’Università, 2, 35020 Legnaro (PD), Italy * Correspondence: [email protected]; Tel.: +39-0532-455354 Received: 15 May 2019; Accepted: 19 June 2019; Published: 21 June 2019 Abstract: Even today, techentium-99m represents the radionuclide of choice for diagnostic radio-imaging applications. Its peculiar physical and chemical properties make it particularly suitable for medical imaging. By the use of molecular probes and perfusion radiotracers, it provides rapid and non-invasive evaluation of the function, physiology, and/or pathology of organs. The versatile chemistry of technetium-99m, due to its multi-oxidation states, and, consequently, the ability to produce a variety of complexes with particular desired characteristics, are the major advantages of this medical radionuclide. The advances in technetium coordination chemistry over the last 20 years, in combination with recent advances in detector technologies and reconstruction algorithms, make SPECT’s spatial resolution comparable to that of PET, allowing 99mTc radiopharmaceuticals to have an important role in nuclear medicine and to be particularly suitable for molecular imaging. In this review the most efficient chemical methods, based on the modern concept of the 99mTc-metal fragment approach, applied to the development of technetium-99m radiopharmaceuticals for molecular imaging, are described. A specific paragraph is dedicated to the development of new 99mTc-based radiopharmaceuticals for prostate cancer. Keywords: technetium-99m; chemistry; radiopharmaceuticals 1. Introduction Molecular Imaging (MI) is a type of medical procedure that provides the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in living systems [1]. Nuclear medicine is a branch of MI that, through the use of radiopharmaceuticals, allows physicians to see and to measure functional, metabolic, chemical, and biological processes within the body and/or to treat malignant tumours, cancer, and other diseases [2–5]. In general, a radiopharmaceutical is a medicinal product that is, usually, administered intravenously to the patient. The radiopharmaceutical is the result of the linkage of two elements, a carrier and at least one radioactive atom that, with its nuclear properties, defines the diagnostic and/or therapeutic nature of the radioactive compound. The carrier plays an important role in the selective transport of the radionuclide to a specific biological target (Figure1). Appl. Sci. 2019, 9, 2526; doi:10.3390/app9122526 www.mdpi.com/journal/applsci Appl. Sci. 2019, 9, x FOR PEER REVIEW 2 of 16 Radioactive atoms decay through a nuclear process that leads to the production of γ-rays used in the diagnostic imaging field. In this case, the radioactivity coming from the radiopharmaceutical, carrying the diagnostic information outward from the body, is detected and transformed in a very precise picture of the radiopharmaceutical’s distribution in the body by means of so-called “gamma cameras” working with sophisticated computerized algorithms. On the contrary, radionuclides decaying through the emission of massive particles, such as electrons or alphas, can be used in nuclearAppl. Sci. medicine2019, 9, 2526 for radionuclide therapy to treat certain types of cancer and other diseases [6–8].2 of 16 Figure 1. Schematic representation of linkage of the carrier and the radioactive atom to form the Figure 1. Schematic representation of linkage of the carrier and the radioactive atom to form the radiopharmaceutical that interacts with a specific biological target. radiopharmaceutical that interacts with a specific biological target. Radioactive atoms decay through a nuclear process that leads to the production of γ-rays used in theIdeally, diagnostic for diagnostic imaging field.nuclear In thismedicine case, theimaging radioactivity applications, coming each from nuclear the radiopharmaceutical, decay should yield acarrying monochromatic the diagnostic gamma-ray information in the energy outward range from 100 the–600 body, keV, is and detected the half-life and transformed of the radionuclide in a very shouldprecise picturebe on ofthe the radiopharmaceutical’sorder of a few hours distribution to avoid in theunnecessary body by means exposure of so-called to radiation. “gamma Radiopharmaceuticalscameras” working with for sophisticatedsingle-photon computerizedcomputed tomography algorithms. (SPECT) On the are contrary,generally radionuclidescomposed of singledecaying small through molecules the emission (the size ofcan massive range from particles, 10−12 such to 10 as−6 m) electrons radiolabelled or alphas, wi canth a begamma-emitting used in nuclear isotope,medicine such for as radionuclide indium-111, therapy iodine-123, to treat gallium-67, certain types or technetium-99m. of cancer and other diseases [6–8]. AdvancedIdeally, for methods diagnostic to nuclearspecifically medicine and selectively imaging applications, incorporate each medical nuclear radionuclides, decay should such yield as a radiometals,monochromatic into gamma-ray targeting invectors, the energy based range on 100–600an improved keV,and understanding the half-life of theof radionuclidetheir coordination should chemistrybe on the orderand ofthe a fewdevelopment hours to avoid of unnecessarycreative labelling exposure strategies, to radiation. are Radiopharmaceuticals the core of modern for radiopharmaceuticalsingle-photon computed research tomography [9–11]. (SPECT) are generally composed of single small molecules (the Among the SPECT12 isotopes6 currently in use, technetium-99m has become the workhorse of size can range from 10− to 10− m) radiolabelled with a gamma-emitting isotope, such as indium-111, diagnosticiodine-123, nuclear gallium-67, medicine or technetium-99m. and technetium-99m-based radiopharmaceuticals are still the most used 99m radioactiveAdvanced chemical methods compounds to specifically in hospitals’ and selectively clinical practice incorporate [12–15]. medical The main radionuclides, reasons for suchTc’s as continuingradiometals, usage into targeting are its ideal vectors, nuclear based onproperti an improvedes and understandingits convenient of supply their coordination method through chemistry a commercialand the development generator system. of creative Techentium-99m labelling strategies, decays arethrough the core the emission of modern of radiopharmaceutical140 keV γ-rays (89% abundance),research [9– 11which]. is ideal for imaging with medical gamma cameras, and can be administered to 99m patientsAmong in low-radiation the SPECT isotopesdoses. Moreover, currently its in 6-h use, half-life technetium-99m is sufficient has for become the preparation the workhorse of Tc of radiopharmaceuticalsdiagnostic nuclear medicine (in hospitals and technetium-99m-basedor centralized radiopharmacies), radiopharmaceuticals their possible aredistribution, still the most the performanceused radioactive of quality chemical controls, compounds administration in hospitals’ to the clinicalpatient, practice accumulation [12–15 in]. Thethe target main organ, reasons and for image99mTc’s acquisition. continuing usageEven areif itsthe ideal use nuclear of radiopha propertiesrmaceuticals and its convenient labelled supplywith positron method throughemitters a radionuclidescommercial generator challenged system. the field Techentium-99m of SPECT tracers, decays over through 70% of the diagnostic emission investigations of 140 keV γ-rays are (89%still performedabundance), with which this issingle ideal isotope for imaging for imaging with medical of bone, gamma renal, cameras,hepatic, andhepatobiliary, can be administered cardiac, and to oncologicalpatients in diseases low-radiation or other doses. pathologies. Moreover, Until its some 6-h half-life years ago, is su theffi cientinferior for sensitivity, the preparation temporal of 99m andTc spatialradiopharmaceuticals resolution of SPECT (in hospitals cameras or compared centralized to radiopharmacies), positron emission their tomography possible distribution,(PET) cameras, the togetherperformance with ofthe quality complex controls, and contrived administration inorganic to the chemistry patient, accumulation of this metal, in were thetarget considered organ, key and image acquisition. Even if the use of radiopharmaceuticals labelled with positron emitters radionuclides challenged the field of SPECT tracers, over 70% of diagnostic investigations are still performed with this single isotope for imaging of bone, renal, hepatic, hepatobiliary, cardiac, and oncological diseases or other pathologies. Until some years ago, the inferior sensitivity, temporal and spatial resolution of SPECT cameras compared to positron emission tomography (PET) cameras, together with the complex and contrived inorganic chemistry of this metal, were considered key problems in the