**1. Introduction**

Molecular baskets based on the calixarene backbone were found to be a promising basis to search for suitable macrocyclic ligands especially for divalent metal ions. Calix[4]arenes are metacyclophanes having a hydrophobic cavity between the lower and upper rim, formed by four phenol units connected with methylene units [1,2]. Due to their numerous possibilities for functionalization on the upper as well as on the lower rim [3], this class of macromolecules is known for a wide range of applications [4,5]. Calix[4]arenes were found to act as biologically active compounds as they are used as antibacterial and even antimalarial agents or in cancer chemotherapy [6–9]. Additionally, they can interact with amino acids or show promising enzyme inhibitory effects [10]. Their ability to form inclusion compounds with neutral molecules [11] or ions [12–16] makes them useful as sensors [17,18], catalysts [19], ligands, or as effective separation agents for ions [20] when resin-bound [21–24]. Since calix[4]arene derivatives interact particularly strongly with heavy group 2 metals [25–31], one major field of application consists in their use as extraction agents for nuclear waste treatment [27,32–35].

In this regard, the calix[4]arene skeleton can be seen as an ideal platform to build an optimized chelator. Two out of the four hydroxy groups on the lower rim are possible to be functionalized with proton-ionizable groups, which leads to the formation of neutral complexes with divalent cations. The remaining two can be furnished with oligo ether groups, either open-chain or bridged, leading to the calixcrown scaffold, which is easily accessible. Using this concept, both the advantages of the electrostatic, macrocyclic, and cryptate effect are unified.

Three divalent cations Sr2+, Ba2+, and Pb2+ are in the focus of our interest, because they all possess radioisotopes with useful nuclear properties for various diagnostic or therapeutic applications in nuclear medicine [36], and are therefore suitable to prepare radiopharmaceuticals. The beta-emitter <sup>89</sup>Sr is applied as "bone seeker" [37], and <sup>90</sup>Sr is used for superficial brachytherapy of some cancers [38,39]. <sup>131</sup>Ba (t1/2 = 11.5 d) is a γ-emitter for possible diagnostic uses and is discussed as a bone-scanning agent in scintigraphy [40–42]. Furthermore, Ba2+ functions as a non-radioactive surrogate [43–45] for both alpha-emitters 223/224Ra, because of their analogous chemical properties and their radii of similar range [46]. Radium-223 and radium-224, have suitable half-lives ( <sup>223</sup>Ra: 11.4 d, <sup>224</sup>Ra: 3.6 d) and nuclear decay properties (decay chain with four alpha and two beta particles) [47] that make them useful tools for alpha-particle therapy [48]. [ <sup>223</sup>Ra]RaCl<sup>2</sup> is known as Xofigo® and is applied in clinics for the treatment of bone metastases. Furthermore, Pb2+ was part of our research. On the one hand, it is the stable end product (207Pb and <sup>208</sup>Pb) of both radium decay chains. On the other hand, <sup>212</sup>Pb is a promising β – -emitter, and a feasible candidate for radiopharmaceutical applications, since it can also be used as an in vivo generator for <sup>212</sup>Bi, which is a strong alpha emitter [49,50]. No indications were found regarding radiopharmaceutical applications of the light alkaline earth metals beryllium, magnesium, and calcium for therapy or diagnosis.

To provide the ideal cavity for heavy group 2 metals for stable complexation, it is essential to choose a suitable oligo ether length or crown size, respectively, combined with an adequate number of donor sites. Recently, the impact of the crown-6-functionalization of two simple calix[4]crown-6 derivatives has been elaborated [29,30]. The group of R. A. Bartsch focused on extraction of alkaline earth metal cations using functionalized calixcrowns [51–53] and found the calix[4]arene-1,3-crown-6 derivatives to be very effective group 2 metal ion extraction agents. The additional impact of two trifluoromethylsulfonylamide groups as proton-ionizing residues was corroborated by them and our research group [26]. Furthermore, these compounds showed high selectivity for Ba2+ over the lighter alkaline earth metal or alkali metal ions. However, Ra2+ was not investigated. There are only a handful of reports dealing with Ra2+ and the efficiency of various ligands including calixarenes as ionophores in nuclear waste management [28,54,55]. Particularly in radiopharmacy, high stability of the complex is urgently important so that a M2+-release and the following accumulation in bone tissues is minimized [42,44].

The objective of this research was to evaluate and compare different open-chain and bridged *p*-tert-butylcalix[4]arene derivatives as possible leading compounds that could, upon further modification, yield viable chelators for the selected divalent metal ions Sr2+ , Ba2+, and Pb2+ in radiopharmaceutical applications and provide information about comparable stability constants. The existing literature about group 2 metal ligands specifically with radium, is focused mainly on extraction studies. Therefore, the UV titration as reliable and constant method for the calculation of stability constants was used to determine association constants for the respective ions. Additionally, theoretical calculations involving Ba2+ as a surrogate for Ra2+ were accomplished to underline the results.
