Towards Clinical Development of Scandium Radioisotope Complexes for Use in Nuclear Medicine: Encouraging Prospects with the Chelator 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic Acid (DOTA) and Its Analogues

Abstract

Scandium (Sc) isotopes have recently attracted significant attention in the search for new radionuclides with potential uses in personalized medicine, especially in the treatment of specific cancer patient categories. In particular, Sc-43 and Sc-44, as positron emitters with a satisfactory half-life (3.9 and 4.0 h, respectively), are ideal for cancer diagnosis via Positron Emission Tomography (PET). On the other hand, Sc-47, as an emitter of beta particles and low gamma radiation, may be used as a therapeutic radionuclide, which also allows Single-Photon Emission Computed Tomography (SPECT) imaging. As these scandium isotopes follow the same biological pathway and chemical reactivity, they appear to fit perfectly into the "theranostic pair" concept. A step-by-step description, initiating from the moment of scandium isotope production and leading up to their preclinical and clinical trial applications, is presented. Recent developments related to the nuclear reactions selected and employed to produce the radionuclides Sc-43, Sc-44, and Sc-47, the chemical processing of these isotopes and the main target recovery methods are also included. Furthermore, the radiolabeling of the leading chelator, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and its structural analogues with scandium is also discussed and the advantages and disadvantages of scandium complexation are evaluated. Finally, a review of the preclinical studies and clinical trials involving scandium, as well as future challenges for its clinical uses and applications, are presented.

Keywords: DOTA; chelating agents; nuclear medicine; scandium imaging and diagnostic agents; scandium radiolabeled complexes production and development; scandium radiopharmaceuticals; scandium theranostic pair.

Figure 8

Representative examples (A–G) of Sc-radiolabeled conjugates between a metal chelator (blue) bound to scandium (Sc) and a targeting moiety (peptide or peptide-like small molecule, maroon). Some of these conjugates have been successfully used in vivo for delivering radionuclides to tumors, for imaging (Sc-44) or therapy (Sc-47) [63,140,141,156,159,160,162]. (Note: the chelator IUPAC names can be found in the “Abbreviations” section).

Figure 1

The differential properties of radionuclides used in nuclear medicine for either Positron Emission Tomography (PET) or Single-Photon Emission Computed Tomography (SPECT). Radionuclides that decay to alpha and beta (electron emission, e⁻) particles are used for radiotherapy, while those which undergo gamma emission and beta decay (positron emission, e⁺) are used for radiodiagnosis [1,29]. Abbreviations: PET: Positron Emission Tomography, SPECT: Single-Photon Emission Computed Tomography, A: Mass number, e⁻: Electron, N: Number of neutrons, X: Parent nucleus, X*: Excited nuclear state of parent nucleus, Y: Daughter nucleus, Z: Atomic number, α: Alpha particle, β: Beta particle, γ: Gamma radiation.

Figure 2

Positron Emission Tomography scan process. The two photons emitted at an angle of 180 degrees are detected at the detector ring. The pulse from the detector reaches the coincidence processing unit, which affords the position information. When an impulse is received simultaneously from two detector blocks, the detector electronics simultaneously monitor signals from each detector block and record counts (red dashed box). Abbreviation: β⁺: Positron.

Figure 3

Detection of a photon by a Single-Photon Emission Computed Tomography scan gamma camera. The camera can detect only photons, which are at a right angle relative to the camera. The blue arrow shows the rotation direction of the camera. Abbreviation: γ: Gamma radiation.

Figure 4

Graphical representation of radiopharmaceutical recognition by a target protein on a cancer cell surface. The graphical illustration shows a cancer cell with a mutant protein on its surface (e.g., an antigen). The radiopharmaceutical consists of the targeting molecule (e.g., antibody against the antigen) carrying a labeled chelating agent-radionuclide complex.

Figure 5

Schematic illustration of the properties, mechanism of binding and mechanism of action of an ideal radiopharmaceutical against cancer. The radiopharmaceutical should be able to emit sufficient radiation dose and destroy the cancer cells in a tumor without affecting normal cells in a healthy tissue.

Figure 6

The effect of a theranostic pair in nuclear medicine, used for the simultaneous diagnosis and treatment of liver cancer. Cartoon images show liver tumors prior- (A) and post-treatment (B) with radioactive elements, in the form of a theranostic pair. The treatment results in elimination or shrinkage of tumors (B). The radioactivity symbol represents the radioisotopes used for radiotherapy and radiodiagnosis.

Figure 7

Summary of the chosen method or path from the production of the radionuclide to its use in nuclear medicine. The procedure involves initially the selection of an appropriate nuclear reaction (e.g., alpha, beta beams), the target precursor, the nuclear methods (e.g., cyclotron, generator), and, subsequently, the recovery/recycling of the target and the produced radionuclide’s isolation and conversion to a chelated complex, ready for application [29,53,64,68,69].