Hepatocellular carcinoma (HCC) is the 5th most common tumour worldwide and has a dark prognosis. For nonoperable cases, metabolic radiotherapy with Lipiodol labelled with β-emitters is a promising therapeutic option. The Comprehensive Cancer Centre Eugène Marquis and the National Graduate School of Chemistry of Rennes (ENSCR) have jointly developed a stable and efficient labelling of Lipiodol with rhenium-188 ( ？MeV) for the treatment of HCC. The major “milestones” of this development, from the first syntheses to the recent first injection in man, are described. 1. Introduction Hepatocellular carcinoma (HCC) is the fifth most common tumour worldwide and even ranks second in terms of mortality [1, 2]. Moreover, only a small number of cases are eligible to curative treatments, such as resection or transplantation. For the rest, a wide range of palliative treatments can be proposed, among which are chemoembolisation and radioembolisation with Lipiodol [3–6]. Lipiodol is an oily medium which has shown to be selectively retained in tumour when administered intra-arterially [7]. Lipiodol has been labelled with iodine-131 [8, 9], rhenium-188 [10, 11], yttrium-90 [12, 13], holmium-166 [14], and lutetium-177 [15]. Some early trials with phosphorus-32 have also been described [16]. However, to date, only the first two have been used in man, the iodine-131-labelled Lipiodol (Lipiocis) having a market authorisation. 188Relabelled Lipiodol seems the most promising one, being able to circumvent the major drawbacks of iodine-131 (long half-life, medium beta energy, strong gamma energy, and cost). Indeed, rhenium-188 has ideal properties for molecular radiotherapy (Eβmax = 2.1？MeV with a maximum tissue penetration of 11？mm, Eγ = 155？keV (15%), 1/2 = 17？h) and has the added advantage of being available on a cost-effective day-to-day basis thanks to its generator mode of production [17]. It has thus attracted much interest [18, 19]. First attempts to label Lipiodol with radioisotopes other than iodine-131 were done with a covalently bond chelate, with disappointing results [12, 20]. It was thus postulated that solubilisation of a lipophilic chelate into Lipiodol would make a suitable “radiolabelling” [21]. Soon after, several teams investigated this promising approach [22, 23]. It is in that context that the Centre Eugène Marquis and the Ecole Nationale Supérieure de Chimie de Rennes (ENSCR) decided to combine respectively their experience on radioembolisation of HCC with 131I-Lipiodol [9, 24–27] and knowledge of technetium and rhenium coordination chemistry [28–31], to
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