The Beginning and Development of the Theranostic Approach in Nuclear Medicine, as Exemplified by the Radionuclide Pair 86Y and 90Y

Frank Rösch, Hans Herzog, Syed Qaim
2017 Pharmaceuticals  
In the context of radiopharmacy and molecular imaging, the concept of theranostics entails a therapy-accompanying diagnosis with the aim of a patient-specific treatment. Using the adequate diagnostic radiopharmaceutical, the disease and the state of the disease are verified for an individual patient. The other way around, it verifies that the radiopharmaceutical in hand represents a target-specific and selective molecule: the "best one" for that individual patient. Transforming diagnostic
more » ... g into quantitative dosimetric information, the optimum radioactivity (expressed in maximum radiation dose to the target tissue and tolerable dose to healthy organs) of the adequate radiotherapeutical is applied to that individual patient. This theranostic approach in nuclear medicine is traced back to the first use of the radionuclide pair 86 Y/ 90 Y, which allowed a combination of PET and internal radiotherapy. Whereas the β-emitting therapeutic radionuclide 90 Y (t 1 /2 = 2.7 d) had been available for a long time via the 90 Sr/ 90 Y generator system, the β + emitter 86 Y (t 1 /2 = 14.7 h) had to be developed for medical application. A brief outline of the various aspects of radiochemical and nuclear development work (nuclear data, cyclotron irradiation, chemical processing, quality control, etc.) is given. In parallel, the paper discusses the methodology introduced to quantify molecular imaging of 86 Y-labelled compounds in terms of multiple and long-term PET recordings. It highlights the ultimate goal of radiotheranostics, namely to extract the radiation dose of the analogue 90 Y-labelled compound in terms of mGy or mSv per MBq 90 Y injected. Finally, the current and possible future development of theranostic approaches based on different PET and therapy nuclides is discussed. like 99m Tc (t 1 /2 = 6.0 h), 123 I (t 1 /2 = 13.2 h), 201 Tl (t 1 /2 = 3.06 d), etc., and positron emitters, like 11 C (t 1 /2 = 20.4 min), 18 F (t 1 /2 = 110 min), 68 Ga (t 1 /2 = 67.6 min), etc., are commonly used. As regards internal radionuclide therapy (endoradiotherapy), in general, radionuclides emitting low-range highly ionizing radiation, i.e., αor β-particles, conversion and/or Auger electrons, have been of great interest. The major problem in internal radiotherapy, however, has been the quantification of radiation dose caused to various organs, mainly due to uncertainties in the measurement of radioactivity from outside of the body of the patient. Although in the case of a few therapeutic radionuclides, e.g., 131 I (t 1 /2 = 8.02 d) and 188 Re (t 1 /2 = 17.0 h), γ-scanning or SPECT has been used to determine the radioactivity distribution in the body, the methodology lacks precision. The uncertainty in radioactivity distribution is still higher for radionuclides decaying by pure β-emission, e.g., 32 P (t 1 /2 = 14.3 d), 89 Sr (t 1 /2 = 50.5 d) and 90 Y (t 1 /2 = 2.7 d), because imaging is usually done through the use of bremsstrahlung. In the early 1990s, thoughts started developing in several laboratories to use an SPECT radionuclide as a surrogate of a therapeutic radionuclide [2], e.g., 111 In (t 1 /2 = 2.8 d), a trivalent metal, as a surrogate of 90 Y, another trivalent metal. The use of an 111 In-labelled monoclonal antibody (MAb) as a surrogate to carry out biodistribution and imaging studies to be able to do therapy planning with the analogue 90 Y-MAb continued for many years and has only recently been abandoned. There has also been discussion about the use of several other metallic radionuclides [3, 4] . Yet, none of those approaches provided patient-individual quantitative data on radiation doses. Within the last few years, the combination of both diagnosis (molecular imaging) and therapy (molecular targeted treatment) using one identical (or similar) molecular targeting vector for the same disease is reflected in the term "theranostics". It is also referred to as "personalized medicine", which proposes the customization of healthcare with medical decisions, practices and/or products being tailored to the individual patient. Diagnostic testing employed for selecting appropriate therapies is referred to as "companion diagnostics" or "theranostics". Customized therapeutic products themselves can fall under personalized medicine, as well. Personalized medicine commonly denotes the use of some kind of technology or discovery, enabling a level of personalization not previously feasible or practical. This includes technologies for producing customized pharmaceutical drug products containing individualized dose levels for one or more drug substances. In the context of radiopharmacy and molecular imaging, the concept is similar: it is a therapy-accompanying diagnosis with the aim of a patient-specific treatment. Using the adequate diagnostic radiopharmaceutical, the disease and the state of the disease are verified for an individual patient. The other way around, it verifies that the radiopharmaceutical in hand represents a target-specific and selective molecule: the "best one" for that individual patient, cf. Figure 1 . Transforming diagnostic imaging into quantitative dosimetric information, the optimum radioactivity (expressed in maximum radiation dose to the target tissue and tolerable dose to healthy organs) of the adequate radiotherapeutical is applied to that individual patient. Finally, post-therapeutic imaging is part of the monitoring of the success of the treatment process for that individual patient. In terms of radiation dosimetry, the radiodiagnostic version of the targeting vector should reflect the pharmacology of the radiotherapeutic version. Technically speaking, the accuracy of the diagnostic information is best when positron-emitting radionuclides are used within the radiopharmaceutical. Chemically speaking, if the diagnostic version is identical to the therapeutic radiopharmaceutical, the imaging data can be used directly to extract the radiation doses of the therapeutic version. This is commonly denoted by the nomenclature of "matched pairs", where the diagnostic and therapeutic radionuclides belong to one and the same chemical element. In 1992, a few researchers at the Research Center Jülich, Germany, came to the idea of combining PET and endoradiotherapy by using a pair of radionuclides of the same element, one emitting positrons and the other β-particles. This paper intends to illustrate the general approach to radiotheranostics, first exemplified for the pair 90 Y/ 86 Y, which allowed a combination of PET and internal radiotherapy. Whereas the β-emitting therapeutic radionuclide 90 Y had been available for a long time, the β + emitter 86 Y (t 1 /2 = 14.7 h) had to be developed for medical application. A brief outline of the various aspects Pharmaceuticals 2017, 10, 56 3 of 28 of development work (nuclear data, cyclotron irradiation, chemical processing, quality control, etc.) is given. In parallel to the nuclear and radiochemical aspects, the paper discusses the methodology introduced to quantify molecular imaging of 86 Y-labelled compounds in terms of multiple and long-term PET recordings. Finally, it highlights the ultimate goal of radiotheranostics, namely to extract the radiation dose of the analogue 90 Y-labelled compound in terms of mGy or mSv per MBq 90 Y injected in an individual patient. Experience was already available at Jülich in the clinical use of 90 Y, but the radionuclide 86 Y needed to be developed for PET studies. In the sections given below, we elaborate the developments in various areas of this systematic work. Pharmaceuticals 2017, 10, 56 3 of 27 quality control, etc.) is given. In parallel to the nuclear and radiochemical aspects, the paper discusses the methodology introduced to quantify molecular imaging of 86 Y-labelled compounds in terms of multiple and long-term PET recordings. Finally, it highlights the ultimate goal of radiotheranostics, namely to extract the radiation dose of the analogue 90 Y-labelled compound in terms of mGy or mSv per MBq 90 Y injected in an individual patient. Experience was already available at Jülich in the clinical use of 90 Y, but the radionuclide 86 Y needed to be developed for PET studies. In the sections given below, we elaborate the developments in various areas of this systematic work.
doi:10.3390/ph10020056 pmid:28632200 pmcid:PMC5490413 fatcat:jf4rjis7enb5blg3wlud7p4gwa