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Radiolabeled tracers targeting the prostate-specific membrane antigen (PSMA) have become important radiopharmaceuticals for the PET-imaging of prostate cancer. In this connection, we recently developed the fluorine-18-labelled PSMA-ligand [18F]PSMA-1007 as the next generation radiofluorinated Glu-ureido PSMA inhibitor after [18F]DCFPyL and [18F]DCFBC. Since radiosynthesis so far has been suffering from rather poor yields, novel procedures for the automated radiosyntheses of [18F]PSMA-1007 have been developed. We herein report on both the two-step and the novel one-step procedures, which have been performed on different commonly-used radiosynthesisers. Using the novel one-step procedure, the [18F]PSMA-1007 was produced in good radiochemical yields ranging from 25 to 80% and synthesis times of less than 55 min. Furthermore, upscaling to product activities up to 50 GBq per batch was successfully conducted. All batches passed quality control according to European Pharmacopoeia standards. Therefore, we were able to disclose a new, simple and, at the same time, high yielding production pathway for the next generation PSMA radioligand [18F]PSMA-1007. Actually, it turned out that the radiosynthesis is as easily realised as the well-known [18F]FDG synthesis and, thus, transferable to all currently-available radiosynthesisers. Using the new procedures, the clinical daily routine can be sustainably supported in-house even in larger hospitals by a single production batch. [ABSTRACT FROM AUTHOR]

[18F]FMTEB, [18F]FPEB, [18F]flumazenil, [18F]DAA1106, [18F]MFBG, [18F]FDOPA, [18F]FMT and [18F]FDA are prepared from the corresponding arylboronic esters and [18F]KF/K222 in the presence of Cu(OTf)2py4. The method was successfully applied using three radiosynthetic platforms, and up to 26 GBq of non-carrier added starting activity of 18F-fluoride. [ABSTRACT FROM AUTHOR]

Salinomycin (1) exhibits a large spectrum of biological activities including the capacity to selectively eradicate cancer stem cells (CSC), making it and its derivatives promising candidates for the development of drug leads against CSC. It has been previously shown that salinomycin and its C20-propargylamine derivative (Ironomycin (2)) accumulate in lysosomes and sequester iron in this organelle. Herein, a library of salinomycin derivatives is reported, including products of C20-amination, C1-esterification, C9-oxidation, and C28-dehydration. The biological activity of these compounds is evaluated against transformed human mammary epithelial HMLER CD24 low /CD44 high cells, a well-established model of breast CSC, and HMLER CD24 high /CD44 low cells deprived of CSC properties. Unlike other structural alterations, derivative 4, which displays a cyclopropylamine at position C20, showed a strikingly low IC 50 value of 23 nm against HMLER CD24 low /CD44 high cells. This study provides highly selective molecules to target the CSC niche, a potential interesting advance for drug development to prevent cancer resistance., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Radiolabeled tracers targeting the prostate-specific membrane antigen (PSMA) have become important radiopharmaceuticals for the PET-imaging of prostate cancer. In this connection, we recently developed the fluorine-18-labelled PSMA-ligand [ 18 F]PSMA-1007 as the next generation radiofluorinated Glu-ureido PSMA inhibitor after [ 18 F]DCFPyL and [ 18 F]DCFBC. Since radiosynthesis so far has been suffering from rather poor yields, novel procedures for the automated radiosyntheses of [ 18 F]PSMA-1007 have been developed. We herein report on both the two-step and the novel one-step procedures, which have been performed on different commonly-used radiosynthesisers. Using the novel one-step procedure, the [ 18 F]PSMA-1007 was produced in good radiochemical yields ranging from 25 to 80% and synthesis times of less than 55 min. Furthermore, upscaling to product activities up to 50 GBq per batch was successfully conducted. All batches passed quality control according to European Pharmacopoeia standards. Therefore, we were able to disclose a new, simple and, at the same time, high yielding production pathway for the next generation PSMA radioligand [ 18 F]PSMA-1007. Actually, it turned out that the radiosynthesis is as easily realised as the well-known [ 18 F]FDG synthesis and, thus, transferable to all currently-available radiosynthesisers. Using the new procedures, the clinical daily routine can be sustainably supported in-house even in larger hospitals by a single production batch., Competing Interests: René Martin, Alexander Hoepping, Sandra Hübner, Anna-Maria Zerges, Rene Smits, Ronny Hesse, A. Hoepping and M. Müller are employees of ABX advanced biochemical compounds GmbH. [F]PSMA-1007 is the subject of a patent application by DKFZ Heidelberg with contributing inventors Jens Cardinale and Klaus Kopka et al. The one-step synthesis method using Precursor 3 is the subject of a patent application by ABX advanced biochemical compounds with contributing inventors René Martin, Ronny Hesse, Rene Smits, Marco Müller and Alexander Hoepping.

We report an efficient synthesis of the hypermodified natural tRNA modifications wybutosine (yW) and hydroxywybutosine (OHyW). We also describe the preparation of isotopically labeled analogues for precise quantification of yW and OHyW in different tissues including plant materials. The synthesis involved the formation of the unusual tricyclic ring structure of the bases by using a catalytic, intramolecular hydroamination reaction. The basis for the synthesis is also a stereoselective coupling reaction that allows the introduction of the fully substituted side chains to the tricyclic core structure. The isotopologues of yW and OHyW, together with other isotopically labeled tRNA modifications, were ultimately used in LC-MS quantification experiments to investigate the role of the modified bases in the translational process. Quantification was performed in the plant species Arabidopsis thaliana., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Useful diversity: Quantification of modified tRNA nucleobases in different murine and porcine tissues reveals a tissue-specific overall modification content. The modification content correlates with rates of protein synthesis in vitro, suggesting a direct link between tRNA modification levels and tissue-specific translational efficiency., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

DNA and RNA contain, next to the four canonical nucleobases, a number of modified nucleosides that extend their chemical information content. RNA is particularly rich in modifications, which is obviously an adaptation to their highly complex and variable functions. In fact, the modified nucleosides and their chemical structures establish a second layer of information which is of central importance to the function of the RNA molecules. Also the chemical diversity of DNA is greater than originally thought. Next to the four canonical bases, the DNA of higher organisms contains a total of four epigenetic bases: m(5) dC, hm(5) dC, f(5) dC und ca(5) dC. While all cells of an organism contain the same genetic material, their vastly different function and properties inside complex higher organisms require the controlled silencing and activation of cell-type specific genes. The regulation of the underlying silencing and activation process requires an additional layer of epigenetic information, which is clearly linked to increased chemical diversity. This diversity is provided by the modified non-canonical nucleosides in both DNA and RNA., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)