Bioorganometallic Technetium and Rhenium Chemistry: Fundamentals for Applications
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RadiochemistRy in switzeRland CHIMIA 2020, 74, No. 12 953 doi:10.2533/chimia.2020.953 Chimia 74 (2020) 953–959 © R. Alberto, H. Braband, Q. Nadeem Bioorganometallic Technetium and Rhenium Chemistry: Fundamentals for Applications Roger Alberto*, Henrik Braband, and Qaisar Nadeem Abstract: Due to its long half-life of 2.111×105 y, technetium, i.e. 99Tc, offers the excellent opportunity of combin- ing fundamental and ‘classical’ organometallic or coordination chemistry with all methodologies of radiochem- istry. Technetium chemistry is inspired by the applications of its short-lived metastable isomer 99mTc in molecular imaging and radiopharmacy. We present in this article examples about these contexts and the impact of purely basic oriented research on practical applications. This review shows how the chemistry of this element in the middle of the periodic system inspires the chemistry of neighboring elements such as rhenium. Reasons are given for the frequent observation that the chemistries of 99Tc and 99mTc are often not identical, i.e. compounds accessible for 99mTc, under certain conditions, are not accessible for 99Tc. The article emphasizes the importance of macroscopic technetium chemistry not only for research but also for advanced education in the general fields of radiochemistry. Keywords: Bioorganometallics · Molecular Imaging · Radiopharmacy · Rhenium · Technetium Roger Alberto obtained his PhD from the Qaisar Nadeem got his PhD from the ETH Zurich. He was an Alexander von University of the Punjab Lahore, Pakistan. Humboldt fellow in the group of W.A. He received the higher education commission Herrmann at the TU Munich and at the (HEC, Pakistan) fellowship during his PhD Los Alamos National Laboratory with and worked in theAlberto group, Department A Sattelberger. He then joined the Paul of Chemistry University of Zurich, on the Scherrer Institute withA. Schubiger in 1991. synthesis of 99mTc complexes of cyclopen- In 2000, he joined the University of Zurich tadienyl-derivatized, bioactive peptides. Dr. and was elected full professor in 2006. He Qaisar Nadeem became Assistant Professor headed the Institute of Inorganic Chemistry of Chemistry for three years at the Islamia from 2006-2013 and the Department of Chemistry from 2012- University of Bahawalpur before moving back to the Alberto re- 2016. Since 2013, he leads ‘LightChEC’, a University Research search group, as a postdoctoral fellow since 2018, he is working on Priority Program. Among others, he was awarded an Alexander the aqueous synthesis of 99mTc bis-arene complexes. von Humboldt research award and the Heilbronner-Hückel lec- tureship of the GDCh. His research interests are synthetic radio- 1. Introduction chemistry, molecular imaging, bioorganometallic chemistry and artificial photosynthesis. 1.1 Historical Development of Technetium Chemistry Technetium is a man-made element, discovered and character- Henrik Braband obtained his PhD from ized by C. Perrier and the Nobel laureate E. Segrè in 1937.[1] Since the Free University of Berlin in 2006. In the it was only available in trace amounts from cyclotron-irradiated same year, he joined the research group of molybdenum foils, some time passed before the exploration of Roger Alberto at the University of Zurich its chemistry on the macroscopic level could start. The first re- (UZH) as a postdoctoral fellow. From ports on technetium chemistry on a weighable scale appeared in 2009–2013 he was an Ambizione fellow the early fifties, when 99Tc became available from the workup of of the Swiss National Science Foundation. spent nuclear fuels.[2] Since about 6% of all fission products is 99Tc, Since 2013, Henrik Braband is group leader chemistry on the gram scale was no problem at that time, especially in the Alberto research group. He is the lab- since the half-life of 2.111×105 y is rather long, making its specific oratory manager of the radiochemistry fa- activity reasonably low. In addition, 99Tc is a weak β–-emitter, the cility and head of radiation safety of the Department of Chemistry radiation of which is essentially absorbed by the walls of normal of UZH. His research interests are synthetic radiochemistry, mo- glassware keeping exposition to ionizing radiation at a reasonable lecular imaging, bioorganometallic chemistry and nanomaterials level when following standard radiochemical radiation protection for (nuclear) medical applications. measures as requested by the authorities. For a long time, tech- netium was considered just an ‘exotic’ artificial element and not too much attention was paid to it. This changed when Brookhaven National Laboratory discovered the 99Mo/99mTc generator and the very favorable properties of the metastable nuclide 99mTc for nu- clear medicine purposes.[3] Since 99mTc has a half-life of only 6 h, *Correspondence: Prof. R. Alberto, E-mail: [email protected] Department of Chemistry, University of Zurich, Winterthurerstr. 190, macroscopic chemistry is impossible. To characterize the authen- CH-8057 Zurich, Switzerland ticities of 99mTc complexes, it is essential to prepare the long-lived 954 CHIMIA 2020, 74, No. 12 RadiochemistRy in switzeRland 99Tc analogues and to compare, e.g. their retention times in ITLC or becoming more and more important since the pure imaging op- HPLC. Recognizing the high importance and convenience of 99mTc portunities with 99mTc are complemented by strongly increasing for nuclear medicine initiated a stormy development in technetium activities exploring the cyto- or phototoxic properties of rhenium chemistry with 99Tc. The main purpose was to fully characterize organometallic compounds as pointed out by Gasser et al.[13] In compounds of 99mTc by studying 99Tc but even more to discover the matched-pair concept, 99mTc complexes would be used for im- and develop new complexes for functional imaging. Fundamental aging and its rhenium homologues for chemotherapy, thus open- coordination compounds and organometallic complexes were syn- ing a unique pathway for theranostics hardly encountered for any thesized and characterized in the seventies, the eighties and the other set of elements.[13,14] This concept requires, however, that the nineties. Numerous groups were active worldwide in technetium compounds have to be prepared with 99mTc in water together with chemistry and reviews appeared regularly about progresses and rhenium, which is not such an easy prerequisite as it might look at advances. Technetium even had its own dedicated conference.[4] first glance (vide infra). Alternatively, matching 99mTc chemistry Despite this thrust for new technetium compounds, many with rhenium could also be a combination with 188Re or 186Re, two fundamental fields remained essentially untouched, in particular radioisotopes with excellent radiotherapeutic properties but dif- those with no immediate perspective of application in nuclear ficult to obtain in appropriate qualities and quantities.[15] medicine. This concerned especially organometallic compounds Labelling with 99mTc is based on several strategies, each of them but also fundamental structures such as the binary halides, which requiring broad skills and interdisciplinary vistas. Originally, the are core in the chemistry of the neighboring transition elements. preparation of new radiopharmaceuticals for imaging purposes Only recently, A. Sattelberger and coworkers filled one of these focused on the synthesis of new complexes, so-called ‘de novo’ gaps with a systematic study about technetium halide preparations radiopharmaceuticals. Cardiolite®, an extremely successful myo- and structures.[5] 99mTc is a nuclide for Single Photon Emission cardial imaging agent, is such an example (Fig. 2A). Cardiolite® Computed Tomography (SPECT). Since the new century, Positron is still in routine clinical application despite being more than Emission Tomography (PET) set out to compete with or rather to thirty years old.[16] De novo radiopharmaceuticals are hardly a complement SPECT. This led to a decreasing relevance of 99Tc topic nowadays since their development is costly and other diag- and 99mTc chemistry. Together with ever-growing radiation safety nostic methods may well compete. A second generation of radio- considerations, fundamental technetium chemistry started to de- pharmaceuticals are targeting molecules such as peptides, pro- cline as well. Despite the fact that still around 80% of all nuclear teins or small molecules which are tagged with a 99mTc complex. medicine diagnoses are done with 99mTc,[6] essentially no new Second-generation radiopharmaceuticals are still topological foci compounds entered the health care market since, among other although, over the years, only a small number of such imaging reasons, basic studies with 99Tc became fewer and fewer. This agents were or are introduced into the market.[17] The labelling of is somewhat surprising since, apart from application-driven re- targeting molecules demands skills in the design and synthesis of search, fundamentals are equally important. Following trends as tailor-made ligands. These have to be conjugated to the biovec- found in other fields, support for fundamental research is more tors without affecting their biological properties. Finally, the new and more difficult to acquire. Nowadays, only a handful of groups conjugates have to be labelled with a 99mTc core and be subjected are still pursuing technetium chemistry with 99Tc, in pure funda- to biological studies. These individual steps have to be combined, mentals[7] or fundamentals directed towards