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The Al 18 F-labeling approach offers a one-step access to radiofluorinated biomolecules by mimicking the labeling process for radiometals. Although these labeling conditions are considered to be mild compared to classic radiofluorinations, improvements of the chelating units have led to the discovery of (±)-H 3 F-labeling already at ambient temperature. While the suitability of RESCA , which allows Al 18 F-labeling, the cyclohexanediamine triazole (CHDT) moiety allows stable complexation of (±)-H 3 RESCA F-, 18 F-labeling, the cyclohexanediamine triazole (CHDT) moiety allows stable complexation of 68 Ga and 111 In. Three novel CHDT-functionalized PSMA inhibitors were synthesized and their Al 18 F-, 68 F-labeled PSMA ligands were characterized for their biodistribution in a LNCaP derived tumor xenograft mouse model by PET imaging. One radioligand, 111 In-labeled analogs were subjected to a detailed in vitro radiopharmacological characterization. Stability studies in vitro in human serum revealed among others a high kinetic inertness of all radiometal complexes. Furthermore, the Al 18 F-labeled PSMA ligands were characterized for their biodistribution in a LNCaP derived tumor xenograft mouse model by PET imaging. One radioligand, Al[ F, 18 F]F-CHDT-PSMA-1 , bearing a small azidoacetyl linker at the glutamate-urea-lysine motif, provided an in vivo performance comparable to that of [ 18 F]PSMA-1007 but with even higher tumor-to-blood and tumor-to-muscle ratios at 120 min p.i. Overall, our results highlight the suitability of the novel CHDT moiety for functionalization and radiolabeling of small molecules or peptides with Al 18 F, 68 Ga, and 111 In and the triazole ring seems to entail favorable pharmacokinetic properties for molecular imaging purposes.

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.)

To pursue the design of in vivo stable chelating systems for radiometals, a concise and straightforward method toolbox was developed combining NMR, isothermal titration calorimetry (ITC), and europium time-resolved laser-induced fluorescence spectroscopy (Eu-TRLFS). For this purpose, the macropa chelator was chosen, and Lu 3+ , La 3+ , Pb 2+ , Ra 2+ , and Ba 2+ were chosen as radiopharmaceutically relevant metal ions. They differ in charge (2+ and 3+) and coordination properties (main group vs lanthanides). 1 H NMR was used to determine four p K a values (±0.15; carboxylate functions, 2.40 and 3.13; amino functions, 6.80 and 7.73). Eu-TRLFS was used to validate the exclusive existence of the 1:1 M n + /ligand complex in the chosen pH range at tracer level concentrations. ITC measurements were accomplished to determine the resulting stability constants of the desired complexes, with log K values ranging from 18.5 for the Pb-mcp complex to 7.3 for the Lu-mcp complex. Density-functional-theory-calculated structures nicely mirror the complexes' order of stabilities by bonding features. Radiolabeling with macropa using ligand concentrations from 10 -3 to 10 -6 M was accomplished by pointing out the complex formation and stability ( 212 Pb > 133 La > 131 Ba ≈ 224 Ra > 177 Lu) by means of normal-phase thin-layer chromatography analyses.

Background: The combination of platinum-containing cytostatic drugs with different radiation qualities has been studied for years. Despite their massive side effects, these drugs still belong to the therapeutic portfolio in cancer treatment. To overcome the disadvantages of cisplatin, our study investigated the cytotoxic effects of combining radionuclides with cisplatin., Methods: FaDu cells were treated with cisplatin (concentration ≈ 2 µM) and additionally irradiated after two hours with the alpha-emitter 223 Ra, the beta-emitter 188 Re as well as external X-rays using dose ranges of 2-6 Gy. Cell survival was followed by colony formation assays and plotted against cisplatin concentration and radiation dose. The results were interpreted by isobolograms., Results: Isobolographic analyses revealed a supra-additive cytotoxic effect for the combination of cisplatin and 223 Ra. A sub-additive effect was observed for the combination of cisplatin and 188 Re, whereas a protective effect was found for the combination with X-rays., Conclusions: The combination of cisplatin and 223 Ra may have the potential to create a successfully working therapy scheme for various therapy approaches, whereas the combination with 188 Re as well as single-dose X-ray treatment did not lead to a detectable radiosensitizing effect. Thus, the combination with alpha-emitters might be advantageous and, therefore, should be followed in future studies when combined with cytostatic drugs.

Theranostic matched pairs of radionuclides have aroused interest during the last couple of years, and in that sense, copper is one element that has a lot to offer, and although 61 Cu and 64 Cu are slowly being established as diagnostic radionuclides for PET, the availability of the therapeutic counterpart 67 Cu plays a key role for further radiopharmaceutical development in the future. Until now, the 67 Cu shortage has not been solved; however, different production routes are being explored. This project aims at the production of no-carrier-added 67 Cu with high radionuclidic purity with a medical 30MeV compact cyclotron via the 70 Zn(p,α) 67 Cu reaction. With this purpose, proton irradiation of electrodeposited 70 Zn targets was performed followed by two-step radiochemical separation based on solid-phase extraction. Activities of up to 600MBq 67 Cu at end of bombardment, with radionuclidic purities over 99.5% and apparent molar activities of up to 80MBq/nmol, were quantified.

Rationale: Small 225 Ac-labeled prostate-specific membrane antigen (PSMA)-targeted radioconjugates have been described for targeted alpha therapy of metastatic castration-resistant prostate cancer. Transient binding to serum albumin as a highly abundant, inherent transport protein represents a commonly applied strategy to modulate the tissue distribution profile of such low-molecular-weight radiotherapeutics and to enhance radioactivity uptake into tumor lesions with the ultimate objective of improved therapeutic outcome. Methods: Two ligands mcp-M-alb-PSMA and mcp-D-alb-PSMA were synthesized by combining a macropa-derived chelator with either one or two lysine-ureido-glutamate-based PSMA- and 4-( p -iodophenyl)butyrate albumin-binding entities using multistep peptide-coupling chemistry. Both compounds were labeled with [ 225 Ac]Ac 3+ under mild conditions and their reversible binding to serum albumin was analyzed by an ultrafiltration assay as well as microscale thermophoresis measurements. Saturation binding studies and clonogenic survival assays using PSMA-expressing LNCaP cells were performed to evaluate PSMA-mediated cell binding and to assess the cytotoxic potency of the novel radioconjugates [ 225 Ac]Ac-mcp-M-alb-PSMA and [ 225 Ac]Ac-mcp-D-alb-PSMA , respectively. Biodistributions of both 225 Ac-radioconjugates were investigated using LNCaP tumor-bearing SCID mice. Histological examinations of selected organs were performed to analyze the occurrence of necrosis using H&E staining, DNA damage via γH2AX staining and proliferation via Ki67 expression in the tissue samples. Results: Enhanced binding to serum components in general and to human serum albumin in particular was revealed for [ 225 Ac]Ac-mcp-M-alb-PSMA and [ 225 Ac]Ac-mcp-D-alb-PSMA , respectively. Moreover, the novel derivatives are highly potent PSMA ligands as their K D values in the nanomolar range (23.38 and 11.56 nM) are comparable to the reference radioconjugates [ 225 Ac]Ac-mcp-M-PSMA (30.83 nM) and [ 225 Ac]Ac-mcp-D-PSMA (10.20 nM) without albumin binders. The clonogenic activity of LNCaP cells after treatment with the 225 Ac-labeled ligands was affected in a dose- and time-dependent manner, whereas the bivalent radioconjugate [ 225 Ac]Ac-mcp-D-alb-PSMA has a stronger impact on the clonogenic cell survival than its monovalent counterpart [ 225 Ac]Ac-mcp-M-alb-PSMA . Biodistribution studies performed in LNCaP tumor xenografts showed prolonged blood circulation times for both albumin-binding radioconjugates and a substantially increased tumor uptake (46.04 ± 7.77 %ID/g for [ 225 Ac]Ac-mcp-M-alb-PSMA at 128 h p.i. and 153.48 ± 37.76 %ID/g at 168 h p.i. for [ 225 Ac]Ac-mcp-D-alb-PSMA ) with favorable tumor-to-background ratios. Consequently, a clear histological indication of DNA damage was discovered in the tumor tissues, whereas DNA double-strand break formation in kidney and liver sections was less pronounced. Conclusion: The modification of the PSMA-based 225 Ac-radioconjugates with one or two albumin-binding entities resulted in an improved radiopharmacological behavior including a greatly enhanced tumor accumulation combined with a rather low uptake in most non-targeted organs combined with a high excretion via the kidneys., Competing Interests: Competing Interests: PSMA-617 is the subject of a patent where K.K. is involved as co-inventor. No other conflicts of interest or competing interests relevant to this article were reported. The other authors have declared that no competing interest exists., (© The author(s).)

Targeted Alpha Therapy is a research field of highest interest in specialized radionuclide therapy. Over the last decades, several alpha-emitting radionuclides have entered and left research topics towards their clinical translation. Especially, 225Ac provides all necessary physical and chemical properties for a successful clinical application, which has already been shown by [225Ac]Ac-PSMA-617. While PSMA-617 carries the DOTA moiety as the complexing agent, the chelator macropa as a macrocyclic alternative provides even more beneficial properties regarding labeling and complex stability in vivo. Lanthanum-133 is an excellent positron-emitting diagnostic lanthanide to radiolabel macropa-functionalized therapeutics since 133La forms a perfectly matched theranostic pair of radionuclides with the therapeutic radionuclide 225Ac, which itself can optimally be complexed by macropa as well. 133La was thus produced by cyclotron-based proton irradiation of an enriched 134Ba target. The target (30 mg of [134Ba]BaCO3) was irradiated for 60 min at 22 MeV and 10−15 µA beam current. Irradiation side products in the raw target solution were identified and quantified: 135La (0.4%), 135mBa (0.03%), 133mBa (0.01%), and 133Ba (0.0004%). The subsequent workup and anion-exchange-based product purification process took approx. 30 min and led to a total amount of (1.2−1.8) GBq (decay-corrected to end of bombardment) of 133La, formulated as [133La]LaCl3. After the complete decay of 133La, a remainder of ca. 4 kBq of long-lived 133Ba per 100 MBq of 133La was detected and rated as uncritical regarding personal dose and waste management. Subsequent radiolabeling was successfully performed with previously published macropa-derived PSMA inhibitors at a micromolar range (quantitative labeling at 1 µM) and evaluated by radio-TLC and radio-HPLC analyses. The scale-up to radioactivity amounts that are needed for clinical application purposes would be easy to achieve by increasing target mass, beam current, and irradiation time to produce 133La of high radionuclide purity (>99.5%) regarding labeling properties and side products.

Ni-rich layered oxide cathodes are promising candidates to satisfy the increasing energy demand of lithium-ion batteries for automotive applications. Aqueous processing of such materials, although desirable to reduce costs and improve sustainability, remains challenging due to the Li + /H + exchange upon contact with water, resulting in a pH increase and corrosion of the aluminum current collector. Herein, an example was given for tuning the properties of aqueous LiNi 0.83 Co 0.12 Mn 0.05 O 2 electrode pastes using a lithium polyacrylate-based binder to find the "sweet spot" for processing parameters and electrochemical performance. Polyacrylic acid was partially neutralized to balance high initial capacity, good cycling stability, and the prevention of aluminum corrosion. Optimized LiOH/polyacrylic acid ratios in water were identified, showing comparable cycling performance to electrodes processed with polyvinylidene difluoride requiring toxic N-methyl-2-pyrrolidone as solvent. This work gives an exemplary study for tuning aqueous electrode pastes properties aiming towards a more environmentally friendly processing of Ni-rich cathodes., (© 2022 The Authors. ChemSusChem published by Wiley-VCH GmbH.)

The increasing application of positron emission tomography (PET) in nuclear medicine has stimulated the extensive development of a multitude of novel and versatile techniques to introduce fluorine-18, especially for the radiolabelling of biologically or pharmacologically active molecules. Taking into consideration that the introduction of fluorine-18 (t 1/2 =109.8 min) mostly proceeds under harsh conditions, radiolabelling of such molecules represents a challenge and is of enormous interest. Ideally, it should proceed in a regioselective manner under mild physiological conditions, in an acceptable time span, with high yields and high specific activities. Special attention has been drawn to 2-fluoroethyl and 3-fluoropropyl groups, which are often the active sites of radiofluorinated compounds. Precursors containing an ammonium leaving group - such as a strained azetidinium or aziridinium moiety - can help to overcome these obstacles leading to a convenient and mild introduction of [ 18 F]fluoride with high radiochemical yields., (© 2022 The Authors. Published by Wiley-VCH GmbH.)

Ni-rich layered oxide cathodes are promising candidates to satisfy the increasing energy demand of lithium-ion batteries for automotive applications. Thermal and cycling stability issues originating from increasing Ni contents are addressed by mitigation strategies such as elemental bulk substitution ("doping") and surface coating. Although both approaches separately benefit the cycling stability, there are only few reports investigating the combination of two of such approaches. Herein, the combination of Zr as common dopant in commercial materials with effective Li 2 WO 4 and WO 3 coatings was investigated with special focus on the impact of different material processing conditions on structural parameters and electrochemical performance in nickel-cobalt-manganese (NCM) || graphite cells. Results indicated that the Zr 4+ dopant diffusing to the surface during annealing improved the electrochemical performance compared to samples without additional coatings. This work emphasizes the importance to not only investigate the effect of individual dopants or coatings but also the influences between both., (© 2021 The Authors. ChemSusChem published by Wiley-VCH GmbH.)

With the exception of beryllium, divalent cations of every alkaline earth metal are characterized by their calcimimetic behavior. Thus, in vivo biodistribution of these cations mostly occurs in form of a massive accumulation in bone tissues, consisting of hydroxyapatite to a major extent. Apart from the lightest elements beryllium and magnesium, animal studies and human studies regarding the overall in vivo behavior were carried out by using radioisotopes of the elements calcium, strontium, barium and radium. To date, only strontium with its radioisotopes and radium gained importance for applications in nuclear medicine, mainly for pain-reducing and palliative treatment of bone metastases. In contrast, barium radioisotopes can be ascertained as useful imaging agents and possible diagnostic analogues for theranostic approaches. This review focuses on the characteristic and chemical behavior of barium compounds, possible radioactive barium isotopes for future applications in nuclear medicine and radiopharmacy as well as recent results regarding barium-131 as diagnostic match for radium isotopes used in targeted alpha therapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Currently, targeted alpha therapy is one of the most investigated topics in radiopharmaceutical cancer management. Especially, the alpha emitter 225 Ac has excellent nuclear properties and is gaining increasing popularity for the treatment of various tumor entities. We herein report on the synthesis of two universal 225 Ac-chelators for mild condition radiolabeling and binding to conjugate molecules of pharmacological interest via the copper-mediated click chemistry. A convenient radiolabeling procedure was investigated as well as the complex stability proved for both chelators and two PSMA (prostate-specific membrane antigen)-targeting model radioconjugates. Studies regarding affinity and cell survival were performed on LNCaP cells followed by biodistribution studies, which were performed using LNCaP tumor-bearing mice. High efficiency radiolabeling for all conjugates was demonstrated. Cell binding studies revealed a fourfold lower cell affinity for the PSMA radioconjugate with one targeting motif compared to the radioconjugate owing two targeting motifs. Additionally, these differences were verified by in vitro cell survival evaluation and biodistribution studies, both showing a higher cell killing efficiency for the same dose, a higher tumor uptake (15%ID/g) and a rapid whole body clearance after 24 h. The synthesized chelators will overcome obstacles of lacking stability and worse labeling needs regarding 225 Ac complexation using the DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid) chelator. Moreover, the universal functionalization expands the coverage of these chelators in combination with any sensitive bio(macro)molecule, thus improving treatment of any addressable tumor target.

We present a case of subcutaneous insulin resistance syndrome, a rare entity, consisting of subcutaneous and intramuscular insulin resistance, with normal or almost normal sensitivity to insulin when administered intravenously. Its cause is unknown and its treatment is challenging. Our patient required a pancreas transplant.

Barium-131 is a single photon emission computed tomography (SPECT)-compatible radionuclide for nuclear medicine and a promising diagnostic match for radium-223/-224. Herein, we report on the sufficient production route 133 Cs( p , 3n ) 131 Ba by using 27.5 MeV proton beams. An average of 190 MBq barium-131 per irradiation was obtained. The SR Resin-based purification process led to barium-131 in high radiochemical purity. An isotopic impurity of 0.01% barium-133 was detectable. For the first time, radiolabeling of the ligand macropa with barium-131 was performed. Radiolabeling methods under mild conditions and reaction controls based on TLC systems were successfully applied. Small animal SPECT/ computed tomography (CT) measurements and biodistribution studies were performed using [ 131 Ba]Ba(NO 3 ) 2 as reference and 131 Ba-labeled macropa in healthy mice for the first time. Biodistribution studies revealed the expected rapid bone uptake of [ 131 Ba]Ba 2+ , whereas 131 Ba-labeled macropa showed a fast clearance from the blood, thereby showing a significantly ( p < 0.001) lower accumulation in the bone. We conclude that barium-131 is a promising SPECT radionuclide and delivers appropriate imaging qualities in small animals. Furthermore, the relative stability of the 131 Ba-labeled macropa complex in vivo forms the basis for the development of sufficient new chelators, especially for radium isotopes. Thereby, barium-131 will attain its goal as a diagnostic match to the alpha emitters radium-223 and radium-224.

Introduction: Radiation-induced DNA damage occurs from direct and indirect effects. The induction is influenced by the physical characteristics of the radionuclide, especially its linear energy transfer. Hypoxia reduces the effect of irradiation treatment in tumor cells and leads to poor patient outcomes. High linear energy transfer emitters can overcome this obstacle. Our aim is to demonstrate the influence of hypoxia on the interaction of different radiation qualities with isolated DNA., Methods: PuC19 Plasmid DNA was irradiated with 223 Ra, 188 Re, 99m Tc and 99m Tc-labeled pyrene with and without DMSO under hypoxia or normoxic conditions. DNA damages in form of single-(SSB) and double-strand breaks (DSB) were analyzed by gel electrophoresis., Results: Radiation doses up to 200 Gy of 223 Ra, 188 Re and 99m Tc led to maximal yields of 80% SSB and 30%, 28% and 32% DSB, respectively. Hypoxia had minor effects on damages from 223 Ra, but caused a small enhancement in DSB for 188 Re and 99m Tc. DMSO prevented DSB completely and reduced SSB from the "free" radionuclides to comparable levels. DNA-binding 99m Tc-labeled pyrene induced less SSB and DSB compared to [ 99m Tc]TcO 4 - . However, the incubation with DMSO could prevent the SSB and DSB induction only to a minor extent., Conclusions: Hypoxia does not limit DNA damage induced by 223 Ra, 188 Re, 99m Tc and 99m Tc-labeled pyrene. Dose-dependent radiation effects were comparable for alpha-emitters and both high- and low-energy electron emitters. The radioprotection by DMSO was not influenced by hypoxia. The results indicate the contribution of mainly indirect radiation effects for 99m Tc, 188 Re and 223 Ra. 99m Tc-labeled pyrene caused direct DNA damages and Auger-electrons from 99m Tc-labeled pyrene are more effective than high-energy electrons or alpha particles., Advances in Knowledge: Without the consideration of DNA repair mechanisms, oxygen has no direct influence in radiation-induced DNA damages by different radiation qualities., Implications for Patient Care: The short-time stimulation with oxygen during patient radiation could have minor influence compared to constant oxygen flooding to overcome hypoxic barriers., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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.

A series of modified calix[4]crown-6 derivatives was synthesized to chelate the heavy group 2 metal barium, which serves as a non-radioactive surrogate for radium-223/-224; radionuclides with promising properties for radiopharmaceutical use. These calixcrowns were functionalized with either cyclic amide moieties or with deprotonizable groups, and the corresponding barium complexes were synthesized. Stability constants of these complexes were measured by using NMR and UV/Vis titration techniques to determine log K values of >4.1. Further extraction studies were performed to characterize the binding affinity of calixcrowns to radioactive barium-133. Additionally, the ligands containing cyclic amides were investigated regarding their rotational barriers by using temperature-dependent NMR measurements.

It is evident that 99mTc causes radical-mediated DNA damage due to Auger electrons, which were emitted simultaneously with the known γ-emission of 99mTc. We have synthesized a series of new 99mTc-labeled pyrene derivatives with varied distances between the pyrene moiety and the radionuclide. The pyrene motif is a common DNA intercalator and allowed us to test the influence of the radionuclide distance on damages of the DNA helix. In general, pUC 19 plasmid DNA enables the investigation of the unprotected interactions between the radiotracers and DNA that results in single-strand breaks (SSB) or double-strand breaks (DSB). The resulting DNA fragments were separated by gel electrophoresis and quantified by fluorescent staining. Direct DNA damage and radical-induced indirect DNA damage by radiolysis products of water were evaluated in the presence or absence of the radical scavenger DMSO. We demonstrated that Auger electrons directly induced both SSB and DSB in high efficiency when 99mTc was tightly bound to the plasmid DNA and this damage could not be completely prevented by DMSO, a free radical scavenger. For the first time, we were able to minimize this effect by increasing the carbon chain lengths between the pyrene moiety and the 99mTc nuclide. However, a critical distance between the 99mTc atom and the DNA helix could not be determined due to the significantly lowered DSB generation resulting from the interaction which is dependent on the type of the 99mTc binding motif. The effect of variable DNA damage caused by the different chain length between the pyrene residue and the Tc-core as well as the possible conformations of the applied Tc-complexes was supplemented with molecular dynamics (MD) calculations. The effectiveness of the DNA-binding 99mTc-labeled pyrene derivatives was demonstrated by comparison to non-DNA-binding 99mTcO4-, since nearly all DNA damage caused by 99mTcO4- was prevented by incubating with DMSO., Competing Interests: The authors have declared that no competing interests exist.