Crown-ethers are well-documented to bind a wide range of cations. However in our hands, we could not detect any binding of [ 201 Tl]Tl(I) by 18-crown-6, dibenzo-18-crown-6 and dicyclohexyl-18-crown-6 under radiolabelling conditions. The group of Brotin has reported an impressive series of different cryptophane derivatives over the last years, including extensive characterization of their ability to bind different cations, including non-radioactive thallium. As the synthesis of these compounds represents a significant challenge, their group kindly provided us with two samples of cryptophanes with which to conduct preliminary studies. While we did observe the appearance of a new peak in the radio-HPLC upon reaction of Crypt1 with [ 201 Tl]Tl(I)Cl, this could only be achieved under strongly basic conditions (Figure ). Adjusting the pH to ~ 7 or exposure to human serum resulted in the release of the thallium cation, hence we did not pursue these chelators any further. Due to the similarities in ionic radii between K(I) and Tl(I) we turned our attention to 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane, more commonly known as Kryptofix 222. This compound was first reported by Sauvage et al in 1969. In this first report the authors described the remarkable propensity of these compounds to form complexes with "metallic cations". Since then, this compound class has found applications in many different fields ranging from crystallography to chemical sensing. Interestingly, its ability to encapsulate potassium ions led to its use as a phase-transfer catalyst for the radiosynthesis of F-fluoro2-deoxy-2-d-glucose ([ 18 F]FDG). Based on these findings we have developed a series of Kryptofix 222 derivatives that can be conjugated to a biological targeting function of choice. Herein we report the synthesis and characterization of these derivatives as well as the preparation of a prostate-cancer targeted analogue. Furthermore, the ability of the Kryptofix compound class to coordinate both non-radioactive and radioactive [ 201 Tl]Tl(I) has been investigated. Before embarking on the synthesis of functionalized derivatives, the ability of commercially available Kryptofix 222 (K222) and Kryptofix 22 (K22, Figure ) to complex [ nat Tl]Tl(I) was investigated by NMR spectroscopy. Addition of TlPF6 in D2O to a solution of the cryptand in D2O resulted in a clear shift in resonances for K222 but only a very small shift for K22 (Supporting Information Figures and). A proof-of-concept radiolabelling study was conducted with K222. Incubation of the cryptand with [ 201 Tl]TlCl in saline led to almost quantitative formation of a new peak with a significantly higher retention time compared to free [ 201 Tl]Tl(I) on reverse-phase radioHPLC (Supporting Information Figure ). Encouraged by these preliminary data we pursued the synthesis of bifunctional K222 chelators. We focused on K222-NH2 as this compound could be conjugated to carboxylic acids via amide-coupling, whilst also offering the possibility to convert it to other synthons for "click"-type coupling reactions i.e. K222-N3 and K222-DBCO (Figure ). The synthetic strategy towards K222-NH2 was based on works by Gansow , Pettit , and Allen adjusted with our own optimisations (Scheme 1). Compound 1 was obtained by reacting 4-nitrocatechol with ethyl bromoacetate in acetone in the presence of sodium carbonate. The reaction could be shortened to 60 min if conducted in a microwave reactor at 180 °C. Hydrolysis to 2 with excess LiOH was straightforward and the chlorination to 3 with thionyl chloride could be achieved after optimization i.e. it was important to keep the reaction refluxing overnight and to directly use the crude product after evaporation of thionyl chloride.