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Objectives Theranostic concepts and the usage of alpha-particle emitting radionuclides belong to the emerging fields of radiopharmaceutical sciences. Especially and due to its excellent complexation properties, the chelator macropa (mcp)[1,2] was reported to be a suitable complexing agent for 225Ac conjugates[3] and as macrocycle a highly promising starting point for the development of 223/224Ra chelators as well. To follow the theranostic approaches with these alpha emitters, due to their chemical similarities 131Ba[4] for SPECT and 133La[5] for PET are available as diagnostic radionuclide surrogates of radium and actinium, respectively. In our recent study, we aim to establish a new workflow to evaluate and predict the complex stability of new chelating systems by obtaining both protonation constants for respective ligands and association constants for their metal complexes starting with mcp. Methods As a prerequisite for the calculation of stability constants (log(K)), the protonation constants (pKa) of mcp were determined by pH‑dependent 1H NMR studies in the first step. Based on these obtained data, the europium-mcp-complex was examined using time-resolved, laser-induced luminescence spectroscopy (TRLFS) and the log(K) was calculated as reference stability constant. Additionally, Eu-TRLFS was used to determine the Eu-mcp species during titration and pH-dependency of the complexation. The method of isothermal titration calorimetry (ITC) was used to measure the complex stability constants of La-, Ba-mcp-complex, as well as Eu-mcp-complex to value the results in comparison with TRLFS data. The evaluation and calculation of the log(K) values were carried out by parallel factor analysis (PARAFAC). Results Depending on the protonation ability of the functional groups found in mcp (amines and carboxylates), pKa values were obtained as well as the log(K) values for the respective mcp-complexes with Ba, Eu and La and are shown in Table 1. Conclusion By combining 1H-NMR, TRLFS and ITC we demonstrated a new approach to fully characterize the ligand, determine metal complex speciation, pKa values for the mcp chelator and log(K) values of the mcp complexes and agree with previous works by potentiometric titration. Furthermore, this method can be transferred to functionalized and improved chelators and their complexes with a wide variety of metal ions of radionuclides used in nuclear medicine, especially the heavy alkaline earth metal ions Ba2+ and Ra2+. Ultimately, this allows a reliable comparison of the individual affinities of the different chelators to the metal ions and thus a predictability of the complex stabilities for future radiopharmaceuticals.

Although significant advances in the tailoring of BaSO4-based nanoparticles have been achieved, the synthesis of particles is strongly dependent on the use of templates, surfactants, and additives, especially when radiolabeled with 133Ba or 224Ra. Herein, direct facile preparation of radiolabeled alendronate-functionalized BaSO4 nanoparticles in an aqueous medium in a one-pot reaction is developed. Remarkably, the size of the formed BaSO4 nanoparticles can be controlled by the type of the organic solvent used. Upon the addition of alendronate, amine functionalities were introduced into the nanoparticles. Additionally, a fluorescence dye-containing alendronate was used to evidence the introduction of the alendronate during the formation of the nanoparticles. The variations in the functionalities were investigated by IR and the morphology of the resulting BASO4 nanoparticles are investigated in detail by transmission electron microscopy. DLS and TEM measurements provided an average diameter of the nanoparticles of approx. 140 nm. Radium-doped alendronate nanoparticles were successfully obtained in a one-pot labeling procedure from [224Ra]RaCl2, Na2SO4 Ba(NO3)2 and alendronate.

Alpha therapy is continually discussed in radiopharmaceutical research. [223Ra]RaCl2 is the only EMA- and FDA-approved alpha-emitting radiopharmaceutical so far. Since the use of 223Ra is only based on its calcimimetic behavior. It is directly bond to bone structures in the body. To enhance the therapeutic potential of radium isotopes, it is necessary to develop novel carrier systems for radium ions as a base of biological targeting units. By the combination of 223Ra or 224Ra, which both have suitable physical half-lives for therapeutic applications, and 131Ba which has a similar half-life but diagnostic radiation properties, a theragnostic idea can also be followed. Our project aims at the synthesis of calixarene-based ligands for the stable complexation of barium and radium ions. Recent studies in our group have already shown the high potential of such ligands.