August P. Schubiger

Current use and future potential of organometallic radiopharmaceuticals

Abstract. Contrary to common belief, organometallic compounds exhibit remarkable stability in aerobic and even diluted aqueous solutions. Technetium-sestamibi (Cardiolite) is one of the most prominent examples of this class of compounds routinely used in nuclear medicine. This review summarises the recent progress in labelling of biomolecules with organometallic complexes for diagnostic and therapeutic application in radiopharmacy and exemplifies in detail developments focussing on organometallic technetium- and rhenium-tricarbonyl technologies. The value of such technologies has been recognised and they have become a valuable alternative to common labelling methodologies. An increasing number of groups have started to employ an organometallic precursor for the purpose of radioactive labelling of various classes of biomolecules, and the advantages and limitations of this new technique are compared with those of other labelling methods. The synthetic access to appropriate precursors via double-ligand exchange or aqueous carbonyl kit preparation for routine application is described. Strategies and examples for the design of appropriate bifunctional chelating agents for the Tc/Re-tricarbonyl core are given. The functionalisation of biomolecules such as tracers for the central nervous system (dopaminergic and serotonergic), tumour affine peptides (somatostatin receptors, neuroreceptors) and tumour binding single-chain antibody fragments is summarised. Where possible and appropriate, the in vitro and in vivo results in respect of these examples are compared with those obtained with classical 99mTc/188Re(V)- and 111In-labelled analogues. The preclinical results show the in many ways superior characteristics of organometallic labelling techniques.

Nuclear medicine 2013: from status quo to status go

For decades nuclear medicine has been fostered as a selfsustaining medical monoculture. Since the 1950s, when focusing on the thyroid gland, nuclear medicine physicians were confident in embracing a holistic approach to the diagnosis and therapy of thyroid diseases. At the time, radionuclide therapy was introduced with the clinical adoption of I-iodide for the diagnosis and therapy of differentiated thyroid carcinoma. This early theranostic concept reflects a prime example of the inherent capabilities of nuclear medicine: to use the same biomolecule both for assessing the extent of a disease and for subsequent image-guided therapy, requiring only its labelling with a different radioisotope. In 1991, a comprehensive review of radiotherapeutics was published [1]. This review described about 40 substances that appeared to be promising probes for various disease pathways. Since then only few therapeutic drugs have been developed and adopted for routine use: I-Iodide and I-MIBG, and another ten radiopharmaceuticals based on radiolabelled phosphonates and Ca analogues (for the treatment of bone metastases) or Y-particles/microspheres (for the treatment of liver metastases). While several radiolabelled antibodies and the first somatostatin analogue were also presented in that early paper [1], it was only in 2012 that the FDA approved of the first Y-radiolabelled antibody (Zevalin) [2]. Today, in 2013, first somatostatin analogues (In/Y-octreotide and Ga/Lu-Tyr-octreotate) are in clinical phase III trials. Also, from an imaging perspective, nuclear medicine has a lot to add to the management of patients. Nuclear medicine imaging techniques, such as SPECT and PET, are instrumental in revealing causes and pathways of a variety of diseases. The clinical success of [F]FDG PET, in particular, has resulted in the wider acceptance of nuclear medicine imaging, and PET in particular, as ameans to provide biological signals as an integral part of disease management. Likewise, the availability of a number of SPECT tracers has supported the adoption of nuclear medicine imaging in diagnostic pathways, such as those in dementia, cardiology and oncology [3]. The success story of PET, and to a somewhat lesser degree of SPECT, is also based on the hardware combination of these modalities with CT. Being fully aware of many of the obstacles to nuclear medicine dissemination, as early as the late 1990s nuclear medicine experts conceived the idea of anatometabolic imaging [4] by means of dual modality imaging systems [5]. In addition to its clinical benefits [6], dual modality imaging offers a number of methodological benefits [7, 8]. Dual modality imaging has further supported the transition towards This editorial represents the essence of the discussions during the 8th Tyrolean Nuclear Medicine Symposium on 28 June 2013 in Innsbruck, Austria, held in honour of the 80th birthday of Prof. Georg Riccabona.