Extraction systems based on organophosphorus compounds (DEHPA, TBP, and TOPO) in HCl and HNO3 were studied for developing a reverse 44Ti/44Sc generator. The 1.8 M TBP-7 M HCl and 0.18 M TOPO-3 M HCl systems demonstrated high separation efficiency in a multistage process and provided 44Sc extraction yields of 96.4 and 93.6% with 44Ti impurities of 8.5 10-3 and 1.8 10-2%, respectively. The daughter 44Sc was quantitatively back-extracted into dilute HCl, providing a ready-to-use solution for subsequent labeling.

Radium-223 is a promising alpha-emitter for targeted alpha therapy (TAT), yet its clinical application is limited by the lack of chelating agents capable of forming stable and kinetically inert complexes under physiological conditions. In this work, we investigated the coordination chemistry of Ra2+, Ba2+, and Ca2+ with a series of rigidified diazacrown ethers featuring acetate (BADA-18/21) and picolinate (BADPA-18/21) pendant arms. The central design strategy utilized an annelated benzene ring to enhance the structural rigidity of the macrocyclic framework and promote effective preorganization of the donor atoms. We demonstrate that picolinate derivatives significantly outperform acetate ones in their affinity for heavy alkaline earth metals. A key finding of this study is that thermodynamic stability constants of Ba2+ complexes are not absolute predictors of radiolabeling efficiency or biological stability for Ra2+ complexes. Despite the high affinity of the 18-membered macrocycle (BADPA-18) for the surrogate Ba2+ ion, only the expanded 21-membered chelator (BADPA-21) provided near-quantitative radiochemical yields (99 +/- 6%) with [Ra-226]Ra2+ within 1 minute at room temperature. The [Ra-226]Ra(BADPA-21) complex exhibited high kinetic inertness in fetal bovine serum and in the presence of biologically relevant metal ions. In vivo biodistribution studies in mice showed that BADPA-21 can at least partially redirect radium from bone and spleen tissues, although its biological stability was found to be moderate compared to macropa. Nevertheless, the combination of exceptionally rapid labeling kinetics under mild conditions and high synthetic accessibility establishes BADPA-21 as a valuable structural lead for the development of improved chelators for TAT.

Nowadays, PSMA ligands are widely used for radiotheragnostic purposes in prostate cancer. The synthesis of a PSMA-Bisp conjugate was developed and realized with good yield (overall yield ~58% for the last two steps). All newly synthesized compounds were characterized by physicochemical methods: 1H and 13C NMR, HRMS, and LCMS (for biologically tested samples). Subsequently, Bisp1 (diacetate bispidine ligand), Bisp-alkyne (bifunctional derivative of Bisp1), and its conjugate PSMA-Bisp were labeled by 64Cu in mild conditions. In vitro studies of the labeled conjugate [64Cu]Cu-PSMA-Bisp have shown great stability in model solutions. Finally, [64Cu]Cu-PSMA-Bisp was compared to the well-known PSMA-617 conjugate labeled with 64Cu and they showed similar stability in excess bovine serum (BVS), and at the same time, labeling PSMA-Bisp with 64Cu is characterized by extremely high kinetics in mild conditions, while labeling PSMA-617 with 64Cu requires heating (90 °C). Thus, this conjugate can be incredibly promising for nuclear medicine.

A series of pyridine-containing diaza-18-crown-6 ethers with acetate, phosphonate, acetamide, and picolinate arms were synthesized and fully characterized for Pb2+ binding to identify their potential for applications in [203/212Pb]Pb-based radiopharmaceuticals. Their coordination chemistry with the Pb2+ ion was investigated by potentiometry, UV-vis spectrophotometry, mass spectrometry, NMR spectroscopy, X-ray diffraction, radionuclide labeling, as well as in vitro and in vivo experiments. It was shown how the nature of the pendant arms and the presence of a rigid pyridyl unit in the macrocyclic structure affect the basicity of the ligands, the efficiency of radiolabeling, the thermodynamic stability of their complexes in aqueous solutions, and their kinetic inertness in biological environments. Consequently, the picolinate macrocycle PADPA was determined to be the most efficient chelating agent for Pb2+, making it a potential candidate for use in radiopharmaceuticals.

With increasing clinical applications and interest in targeted alpha therapy, there is growing interest in developing alternative chelating agents for [212Pb]Pb2+ and [212/213Bi]Bi3+ that exhibit rapid radiolabeling kinetics and kinetic inertness. Herein we report the synthesis and detailed investigation of diacetate and dipicolinate 18- and 21-membered macrocyclic chelators BADA-18, BADA-21, BADPA-18, and BADPA-21 for the complexation of Pb2+ and Bi3+ ions with potential use in the preparation of radiopharmaceuticals. The formation of mononuclear complexes was established by using ESI-mass spectrometry, and their stability constants were determined by potentiometric titration. A thorough study of the structure of the metal complexes was carried out by using X-ray diffraction and NMR spectroscopy. It was shown how the stability of the complex is influenced by an increase in the size of the macrocycle, the replacement of acetate arms with picolinate ones, the rigidity of the ligand, as well as the type of conformation (syn- or anti-) of the metal complex. The new ligands were radiolabeled with [210Pb]Pb2+ and [207Bi]Bi3+, and the in vitro stability of the resulting complexes in a competitive environment of serum and biologically significant metal ions was assessed. Rapid complex formation in 1-2 min at room temperature, as well as the high kinetic inertness of the complexes Pb(BADPA-18) and Bi(BADPA-18) in biological media, demonstrate its potential for use in targeted radionuclide therapy.

In this article, we present the synthesis and characterization of new acyclic pyridine-containing polyaminocarboxylate ligands H4aPyta and H6aPyha, which differ in structural rigidity and the number of chelating groups. Their abilities to form complexes with Cu2+, Ga3+, Y3+, and Bi3+ cations, as well as the stability of the complexes, were evaluated by potentiometric titration method, radiolabeling with the corresponding radionuclides, in vitro studies, mass spectrometry, and HPLC. The structures of the resulting complexes were determined using NMR spectroscopy and DFT calculations. The results obtained made it possible to evaluate the influence of the structural features of the complexes on their stability. The developed chelators H4aPyta and H6aPyha were proved to be promising for further research in the field of radiopharmaceuticals.

Nowadays PSMA ligands are widely used for radiotheragnostic purposes of prostate cancer. The goal of this study was to synthesize and estimate stability in vitro of copper complex with diacetate bispidine ligand (Bisp1), its bifunctional derivative (Bisp-alkyne) and its conjugate – bispidine-PSMA ligand (PSMA-Bisp) to evaluate the possibility of applying one as radiotheragnostic agent. The synthesis for PSMA-Bisp conjugate was developed and realized with good yields. All newly synthesized compounds were characterized by a set of physicochemical methods: 1H and 13C NMR, HRMS and LCMS (for final molecules). Subsequently, Bisp1 and Bisp-alkyne and its derivative PSMA-Bisp were labelled by 64Cu at mild conditions. In vitro studies of the labelled conjugate [64Cu]Cu-PSMA-Bisp have shown the great stability in model solutions. Finally, [64Cu]Cu-PSMA-Bisp was compared to well-known PSMA-617 conjugate labelled with 64Cu and they have showed similar stability in excess of bovine serum (BVS), and at the same time labelling PSMA-Bisp with 64Cu is characterized by extremely high kinetics at mild conditions, while labeling PSMA-617 with 64Cu requires heating (90 °C) [PMCID: PMC5435610]. Thus, the conjugate PSMA-Bisp could be promising candidate for further investigations expanded in vitro and in vivo investigations.

Brachytherapy, or intratumoral radiation therapy, is a highly effective treatment option for localized tumors. Herein, we engineered injectable and biodegradable metal-organic frameworks (MOFs) to deliver the therapeutic radioisotope yttrium-90 (90Y). Particles of bimetallic MIL-100(Fe,Y) and Y-BTC, doped with 90Y and 88Y, were synthesized in a single step and retained radioyttrium in various buffer solutions. Tumor injectability and radioisotope retention were evaluated using tumor-bearing mice. In vivo analysis and calculations showed that radiolabeled MIL-100(Fe,Y) emitted more than 38% of its radioactivity, while Y-BTC emitted greater than 75% of its radioactivity, through 7 days at the tumor site upon intratumoral injection, without significant yttrium accumulation in off-target tissues. The anticancer effects of MIL-100(Fe,Y,90Y) and 90Y,Y-BTC particles were assessed using 3D multicellular tumor spheroids and a tumor-bearing mouse model, respectively. 90Y-doped MIL-100(Fe,Y) particles penetrated A549 tumor spheroids and caused superior cytotoxic effects compared to non-radioactive particles or 90YCl3, added at the same dose. Brachytherapy with 90Y-doped Y-BTC MOFs induced inhibition of B16F1 melanoma tumor growth and resulted in an increased median survival of 8.5 days compared to 4.5 days in untreated mice. This study exhibits the feasibility to prepare radioactive 90Y-containing biodegradable, non-toxic MOF particles that are advantageous for low-dose rate internal radiotherapy. ### Competing Interest Statement The authors have declared no competing interest.

Введение. Проведен синтез конъюгата, состоящего из метотрексата и бифункционального хелатирующего агента. Подобное соединение отличается свойством таргетности по отношению к очагам аутоиммунных артритов. Цель работы – синтезировать комплекс, содержащий радионуклид лютеций-177, для терапии аутоиммунных артритов. Методика. После проведения синтеза радиохимическую чистоту полученного препарата определяли методом тонкослойной хроматографии. В исследованиях in vivo в качестве тест-системы были задействованы аутбредные крысы, самцы в количестве 12 особей. Перед началом исследования животные были распределены на контрольную группу и исследуемую по биораспределению. Исследование биораспределения радиоконъюгата производилось общепринятым способом прямой радиометрии. Оценка производилась путем прямого сравнения распределения радиофармацевтического препарата в крови и органах животных. С учетом периода полураспада радионуклида 177Lu исследования в контрольных точках при изучении фармакокинетики и биораспределения тестируемых препаратов оценивалось не менее 3 особей животных. Результаты. Радиохимическая чистота синтезированного препарата составила не менее 95%. Исследования биораспределения показали тенденции к накоплению препарата в ткани почек, сердца, легких, в остальных оцениваемых органах и тканях накопление препарата имело умеренный и транзиторный характер. Терапевтический радиофармацевтический препарат продемонстрировал удовлетворительный уровень эффективности в отношении целевой нозологии: отмечалось клинически значимое улучшение и частичное восстановление функций пораженной конечности. Заключение. Результаты исследования могут быть внедрены в практику научной работы по разработке лекарственных средств и средств медицинского применения и являются основанием для проведения расширенного углубленного исследования и оптимизации механизмов таргетного действия исследуемых в данной работе радиофармацевтических лекарственных препаратов. Background. A conjugate consisting of methotrexate and a bifunctional chelating agent was synthesized. This compound is distinguished by its ability to target foci of autoimmune arthritis. Aim. To synthesize a radionuclide 177Lu-based complex for the treatment of autoimmune arthritis. Methods. After synthesis, the radiochemical purity of the complex was determined by thin layer chromatography. In the in vivo study, 12 outbred male rats were used as a test system. Prior to the biodistribution study, the animals were divided into a control group and a study group. The radioconjugate biodistribution was assessed with the generally accepted method of direct radiometry by direct comparison of radiopharmaceutical distribution in blood and organs. Taking into account the 177Lu half-life, at least three animals were assessed at measurement points when studying the radiopharmaceutical pharmacokinetics and biodistribution. Results. The radiochemical purity of the 177Lu-based complex was no less than 95%. Biodistribution studies showed a tendency towards radioactivity accumulation in the kidneys, heart, and lungs. In the remaining assessed organs and tissues, the radioactivity accumulation was moderate and transient. The therapeutic radiopharmaceutical demonstrated a satisfactory effectiveness in relation to the target nosology, autoimmune arthritis, evident as clinically significant improvement and partial restoration of the functions of the affected limb. Conclusion. The results of the study can be implemented in the practice for the development of drugs and medical devices and justify conducting an expanded study and optimizing the mechanisms for targeted action of the radiopharmaceuticals, such as studied in the present work.

Thz-Phe-D-Trp-Lys-Thr-DOTA, a conjugate of the DOTA chelator and the Thz-Phe-D-Trp-Lys-Thr pentapeptide, was labeled with 152Eu and 161Tb radionuclides, where 161Tb has decay characteristics suitable for its use in cancer therapy. For the [152Eu]Eu-Thz-Phe-D-Trp-Lys-Thr-DOTA complex, the biodistribution in nude mice bearing IMR-32 tumors was evaluated for the first time. It was shown that the complexes of the conjugate demonstrate accumulation in the tumor at the level of DOTA-TATE, another peptide conjugate widely used in nuclear medicine for the diagnosis and therapy of neuroendocrine tumors, which allows Thz-Phe-D-Trp-Lys-Thr-DOTA to be considered as a potential biological vector for radiopharmaceuticals.

Catecholamines–dopamine, noradrenaline and adrenaline are important biomarkers of neurotransmitter metabolism, indicating neuroendocrine tumors and neurodegenerative diseases. Surface-enhanced Raman spectroscopy (SERS) is a promising analytical technique with unprecedented multiplexing capabilities. However, not all important analytes exhibit strong SERS signals on stable and robust nanostructured substrates. In this work, we propose a novel indicator system based on the formation of mixed ligand complexes with bispidine-based bis-azole ligands which can serve as pliers to trap Cu(II) ions and stabilize its complexes with catecholamines. Four synthesized ligands with different functional groups: carboxyl, amino, benzyl, and methoxybenzyl, were applied for forming stable complexes to shift maximum absorbance of catecholamines from the ultraviolet region to 570–600 nm. A new absorbance band in the visible range resonates with the local surface plasmon resonance (LSPR) band of metal nanoparticles and most used laser wavelengths. This match allowed use of Molecular Immobilization and Resonant Raman Amplification by Complex-Loaded Enhancers (MIRRACLE) methodology to measure intense Raman signals on a nanostructured silver-based SERS-active substrate. The synthesized plier-like ligands fixed and stabilized catecholamine complexes with Cu(II) on the SERS sensor surface, which facilitated the determination of dopamine in a 3.2 × 10−12–1 × 10−8 M concentration range.

In the current research, we conducted a comparative study of the Ac3+ complex with H4DOTA and H4BATA. The stability constants of the [AcBATA]- and [AcDOTA]- complexes were studied directly by extraction methods. We discovered that the thermodynamic properties of the [AcBATA]- complex are superior to those of [AcDOTA]-. Moreover, the fast kinetics of H4BATA complexation with Ac3+ during the radiolabeling experiment was observed already at room temperature. Ac3+ was placed inside the macrocyclic cavity of the [AcBATA]- complex, preventing the release of the cation. According to DFT studies, two possible conformations were found, where two pendant arms coordinate with the metal cation on one side of the azacrown cavity and two on the other side, or three pendant arms are located on one side and one on the other. Finally, high inertness in vitro and in vivo of [AcBATA]- was discovered, making the H4BATA ligand highly preferable for application as a component of actinium-based radiopharmaceuticals.

The paper describes the method developed for obtaining the medical radionuclide 177 Lu, which is obtained using an indirect method, namely, by irradiating an ytterbium target with a high degree of enrichment in the target isotope 176 Yb. This method makes it possible to obtain a radionuclide without a carrier and with a high radionuclide purity for obtaining therapeutic complexes for the purposes of nuclear medicine.

In this work, we synthesized two new benzo-18-azacrown-6 ethers bearing picolinate and pyridine pendant arms and studied the copper complexes of these ligands, as well as those of an acetate analog. All considered ligands were capable of forming mono- and dinuclear complexes due to their large size and large number of donor sites. Among all forms of complexes, the coordination of cations inside the macrocycle has only been shown for the mononuclear form of the acetate complex, while out-cage coordination has been observed for other forms. Electrochemical studies have shown the instability of the mononuclear form of the complex with the pyridine ligand to the reduction in the range of redox potentials of bioreductants. The stabilities of labeled acetate complexes with "in-cage" coordination of the cation and picolinate with "out-cage" coordination were compared in an excess of serum and superoxide dismutase; while the former turned out to be unstable to transchelation, the latter was stable throughout the experiment. Additional studies in biologically relevant media were performed for the picolinate complex and demonstrated its stability in vitro. The biodistribution of this complex in mice after 6 hours post-injection demonstrates a slow excretion from the body; however, the accumulation is noticeably lower than that of free copper cations.

Introduction: The feasibility of preparing the “in-house” generators and the Th- DTPA(DOTA)-Nimotuzumab radioimmunoconjugate was evaluated. 226Th is perspective for TAT, however, due to short half-life it is preferable to apply this radionuclide for readily available epithelial malignancies. Nimotuzumab being specific for EGFR expressing cells as a targeting moiety is considered to be suitable for thorium delivery. Methods: TEVA extraction chromatographic resin and anion exchange resin AG 1x8 were used as sorbents for 226Th generator. In order to determine features of labeling by Th4+ we applied 234Th as a longer-lived analog of short-lived 226Th and the immunoconjugates DTPA(DOTA)-Nimotuzumab were used for radiolabeling. Results: The generator on the base of TEVA resin has shown higher volume activity of the product compared to the AG 1x8. The 226Th volume concentration was up to 80%/mL. The radiolabeling of BFCA by thorium radioisotopes reached 95% at the MR(Th:p-SCN-Bn-DTPA) = 1:100 and 86% for MR(Th:p-SCN-Bn-DOTA) = 1:5000 at 90°C. The procedure of Nimotuzumab labeling with Th4+ for radiotherapy of EGFR-overexpressing carcinomas was established. The overall labeling yield in both radioimmunoconjugates - DTPA and DOTA functionalized - was in the range of 45-50%. The immunoconjugate Nimotuzumab-p-SCN-Bn-DTPA was obtained with a molar ratio 1:25 (Nimotuzumab: BFCA), within 1 hour of conjugation at 25¹C and labelled via postconjugation approach. Whereas Nimotuzumab-p-SCN-Bn-DOTA was obtained at the same conditions, but radiolabeled by the method of pre-conjugation. Conclusion: Thorium-234 incorporation into both radioimmunoconjugates reached 45-50%. It has been shown that Th-DTPA-Nimotuzumab radioimmunoconjugate specifically bound with EGFR overexpressing epidermoid carcinoma A431 cells.

The production possibility of 161Tb and 155Tb by irradiating of natural dysprosium with gamma rays obtained by decelerating an electron beam with an energy of 55 MeV has been demonstrated experimentally. The yield of 161Tb was 14.4 x 103 Bq x mu A-1 x h-1 x cm2 x gDy2O3- 1. Simultaneously, upon irradiation, 155Dy is formed with the yield of 25 x 103 Bq x mu A-1 x h-1 x cm2 x gDy2O3- 1, which leads to the formation of 1.6 x 103 Bq x mu A-1 x h-1 x cm2 x gDy2O3- 1 of 155Tb. It has been shown that the isolation of terbium radioisotopes from tens of mg of dysprosium target can be achieved by extraction chromatography, and final separation yield was 39%. The impurity of 160Tb is 7.3% of the 161Tb activity at EOB.

In current research, we determined the stability constants and kinetic properties of Bi3+ complexes with the benzoazacrown ligand H(4)BATA along with the H(4)DOTA ligand. Correct determination of the stability constants is possible when equilibrium with the free forms of the cation is observed. Unlike potentiometric titration, it is possible to apply the free-ion selective radiotracer extraction (FISRE) method with highly stable complexes at low pH values, where the true equilibrium with the free cation forms in the solution is achieved. FISRE clarified the stability constants of Bi3+ complexes with H(4)BATA towards higher values. According to the UV spectroscopy data, the H(4)BATA ligand binds Bi3+ at room temperature within a few minutes at pH 1. We also defined the acid-assisted mechanism of complex dissociation, where monoprotonated and deprotonated forms of the complex were found to be inert. In summary, the H(4)BATA ligand is highly suitable for use as a component of bismuth-based radiopharmaceuticals.