Matched Pair Theranostics.

Abstract

The principles of personalized medicine, companion diagnostics or theranostics can be almost ideally realized in the field of nuclear medicine. Radionuclides coupled to a specific vector, which can be a small molecule such as glucose or a peptide, or a large molecule, such as an antibody or antibody fragment, can be used to first image and thus diagnose a patient. It is the intent of the diagnosis to make biochemical processes visible in the organism without interference. If the vector is labelled with a therapeutic radionuclide of the same element as the diagnostic one, the biological behavior can be assumed to be nearly identical, as different isotopes of an element exhibit nearly the same kinetics and chemical reactivity. With therapy, one would like to kill tumor cells without side effects. Therefore, in the future, it should be possible to predict the therapeutic response of a patient to an applied radiation dose based on data from nuclear imaging. Furthermore, by imaging the patient after a radionuclide therapy, the progress of the treatment can be assessed, and, if needed, a second or third therapy cycle administered. Follow-up diagnosis allows monitoring of the progression-free survival. Inspection of the chart of nuclides reveals very few cases of true theranostic pairs if applying the following criteria: the diagnostic radionuclide should be a low-energy positron emitter suitable for Positron Emission Tomography / Computed Tomography (PET/ CT) or Positron Emission Tomography / Magnetic Resonance Imaging (PET/MRI) with a half-life in the range of 2 to 24 h. The positron branching should be high and the number of accompanying gamma-rays should be low. Furthermore, its production should be easily accomplished with good yield at a low energy particle accelerator, such as a medical cyclotron in no-carrier added form. Its therapeutic counterpart should be a beta minus – and/or Auger electron emitter with a half-life in the range of 2 to 10 days, again featuring no or only low energy, low intensity accompanying gamma-rays. The production of the radionuclide must be accomplished in large quantities, i.e. TBq per production run in no-carrier added quality. Very advantageous is furthermore an already established labelling chemistry using thermodynamically and kinetically very stable chelators, such as the DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) chelator. The available radionuclide pairs are illustrated in Fig. 1 together with some other commonly used diagnostic and therapeutic radionuclides. To reach the goal of theranostics, new radionuclides with optimum decay characteristics and chemical properties are essential. Their availability is presently very limited, especially in Switzerland, which is entirely lacking adequate production facilities for therapeutic radionuclides, such as Lu or I to name a few. A stable and sustainable supply of radionuclides in quantity and quality suitable for medical applications represents a major effort and remains a scientific challenge. Commonly, diagnostic radionuclides are either derived from a generator system, i.e. from a Mo generator for Tc-labelled products used for diagnosis with single photon emission computed tomography (SPECT), or a Ge-generator for Ga-labelled products for diagnosis by PET. Quite often, PET diagnostic radionuclides, such as the most common F (but also C, and rarely N, O, Cu or Zr), are produced by medical cyclotrons hosted by hospitals or industrial production sites. Therapeutic radionuclides, which are administered in much higher doses with respect to diagnostic ones, are usually produced in nuclear research reactors. Prominent examples are I, Lu or Sm, while Y is derived from a Sr generator system. Currently so-called ‘matched pairs’ are in use to perform theranostics. In this case, not true isotopic pairs are being used, but chemically very similar elements are combined, i.e. making use of the very good stability of the DOTA chelator with elements in the +3 oxidation state, such as Ga, Sc, Y, Lu, Tb or Ac. Currently, Ga-labelled compounds for PET diagnostics are combined with their Lu-labelled counterpart for radionuclide therapy, where routinely a standard dose between 5.55–7.4 GBq is administered.[1] An example are PET diagnostic interventions with Ga-labelled compounds such as [Ga]GaDOTA-TOC (DOTA,Tyr-octreotide) or [Ga]Ga-DOTA-TATE (DOTA,Tyr,Thr-octreotide)[2] for the diagnosis of metastasized neuroendocrine tumors. Recently, diagnosis with [Ga] Ga-PSMA-11[3] for metastasized prostate cancer was followed successfully by treatment with the alpha-particle emitter Ac in the form of [Ac]Ac-PSMA-617 (Fig. 2).[4] The decisive factor to enable future true theranostics lies in the everyday and year-round availability of the respective radionuclides. The following promising candidates contained in Fig. 1 are discussed in more detail.