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In a recent paper in this journal ( RSC Med. Chem. , 2023, 14 , 2429), we described an unusually strong impact of regiospecific exchange of phenylalanines by tyrosines in 10 gallium-68-labeled trimers of certain cyclic RGD peptides, c[XRGDLAXp( N Me)K] (X = F or Y), on non-specific organ uptakes. We found that there was, in part, no correlation of liver uptake with established polarity proxies, such as the octanol-water distribution coefficient (log  D ). Since this observation could not be explained straightforwardly, we suggested that the symmetry of the compounds had resulted in a synergistic interaction of certain components of the macromolecules. In the present work, we investigated whether a comparable effect also occurred for a series of 5 tetramers labeled with lutetium-177. We found that in contrast to the trimers, liver uptake of the tetramers was well correlated to their polarity, indicating that the unusual observations along the trimer series indeed was a unique feature, probably related to their particular symmetry. Since the Lu-177 labeled tetramers are also potential agents for treatment of a variety of αvβ6-integrin expressing cancers, these were evaluated in mice bearing human lung adenocarcinoma xenografts. Due to their tumor-specific uptake and retention in biodistribution and SPECT imaging experiments, these compounds are considered a step forward on the way to αvβ6-integrin-targeted anticancer agents. Furthermore, we noticed that the presence of tyrosines in general had a positive impact on the in vivo performance of our peptide multimers. In view of the fact that a corresponding rule was already proposed in the context of protein engineering, we argue in favor of considering peptide multimers as a special class of small or medium-sized proteins. In summary, we contend that the performance of peptide multimers is less determined by the in vitro characteristics (particularly, affinity and selectivity) of monomers, but rather by the peptides' suitability for the overall macromolecular design concept, and peptides containing tyrosines are preferred., Competing Interests: N. G. Q. and J. N. are inventors on patent applications related to αvβ6-integrin binding peptide conjugates and 68Ga-Trivehexin. J. N. and J. Š. are CSO and CEO, respectively, and co-founders of TRIMT GmbH (Radeberg, Germany) who has licensed IP from TU Munich. J. N. is furthermore a member of the Scientific Advisory Board of Radiopharm Theranostics LLC (Carlton, Australia) who has licensed IP from TRIMT GmbH. S. K. receives research support from TRIMT GmbH., (This journal is © The Royal Society of Chemistry.)

Inspired by the good performance of argyrodites as ion conducting thermoelectrics and as solid electrolytes we investigated the effect of isovalent S 2- substitution for Se 2- in Cu 7 PSe 6 . At room temperature Cu 7 PSe 6 crystallizes in the primitive cubic β-polymorph of the argyrodite structure and transforms to the face-centered high-temperature (HT) γ-modification above 320 K. The transition for the homologous Cu 7 PS 6 occurs at 510 K. Promising thermoelectric and ion conducting properties are observed only in the HT modification, where the cations are mobile. Using Rietveld refinements against X-ray diffraction data the effect of isovalent S 2- substitution for Se 2- on the structural and transport properties in Cu 7 PSe 6-x S x was analyzed. While a step-wise incorporation of S 2- showed typical behavior for a homogeneous solid solution series, the analysis of the diffraction data gave clear evidence of anion ordering due to site preference of the sulfide ions, which can be rationalized using Pearson's HSAB concept. This leads to a stabilization of the HT structure even at lower temperatures. This selective control enables new strategies for the design of argyrodite materials, as isovalent substitution not only allows an engineering of properties, but also permits the stabilization of the polymorph with the most promising properties.