Synthesis, metal complexation and biological evaluation of a novel semi-rigid bifunctional chelating agent for 99mTc labelling

A novel bifunctional chelating agent bearing an aromatic ring has been synthesised and characterised. This ligand formed well-defined oxorhenium complexes. The analogous 99mTcO-complex was obtained in an excellent yield with high radiochemical purity (>95%). The biodistribution of the 99mTo-complex after intravenous injection studied in normal rats showed that the activity was excreted mainly via renal-urinary pathway indicating its use for labelling peptides with 99mTc

First examples of neutral rhenium(V) complexes with a novel semi-rigid ligand containing a P,N,N,S donor atom set: Synthesis, characterisation and crystal structure

A new PN2S ligand, N-[2-(diphenylphosphino)phenyl]-2-[(S-trityl)acetylamino]ethanamide [Ph-P(Ph2)N2S(Trt)], was synthesised and reacted with ReV precursors. The reaction of both tritylated and detritylated ligands with ReOCl3(PPh3)2 gave the same expected neutral complex [ReO{Ph-P(Ph2)N2S}] (4) in good yield. An unexpected neutral and diamagnetic species, [ReN{Ph-P(Ph2)N2S(Trt)}] (5), has been isolated during the complexation of the tritylated ligand with ReNCl2(PPh3)2. The complexes, characterized by classical spectroscopic methods and X-ray analysis for 4, are the first examples of neutral semi-rigid-PN2S rhenium(V) complexes

Ethylenediamine- and propylenediaminediacetic acid derivatives as ligands for the "fac-[M(CO)3]+" core (M = Re, 99mTc)

The reaction of Re(CO)5Cl with o- or p-N-(nitrophenyl)ethylenediaminediacetic acid (H2L1, H2L2) and o- or p-N-(nitrophenyl)propylenediaminediacetic acid (H2L3, H2L4) in methanol leads to the formation of stable anionic [Et3NH][Re(CO)3(L)]·H2O complexes 1-4. These compounds have been characterized by means of IR, mass spectrometry, elemental analysis, NMR and conductimetry, as well as X-ray crystallography for 2 and 3. The [Re(CO)3]+ moiety is coordinated via the nitrogen of the iminodiacetic acid unit and two oxygens of monodentate carboxylate groups. In each case, the nitro group of the aromatic ring remains uncoordinated. The analogous technetium-99m complexes 1' and 3' were also prepared quantitatively by the reaction of H2L1 and H2L3, respectively, with the fac-[99mTc(CO)3(H2O)3]+ precursor in ethanol. The corresponding Re and 99mTc compounds were shown to possess the same structure by means of HPLC studies. The high affinity of these ligands for the Tc(I) or Re(I) core, coupled with the easiness of their derivatization (by reduction of the nitro group in amino group), implies that the utilization of this ligand system to develop target-specific radiopharmaceuticals for diagnosis and therapy is promising

Sodium [2-(mercaptomethylcarbonylamino)-N-(2-mercaptophenyl)ethanamide(4-)-[kappa]4S,N,N',S']oxorhenate(V) monohydrate

In the complex anion of the title compound, Na[Re(C10H8N2O2S2)O]·H2O, the Re atom adopts a square-pyramidal coordination, in which the Re=O bond is apical and the S,N,N,S-tetradentate ligand spans the four basal sites. The Na+ counter-ion is octahedrally surrounded by one S and five O atoms

Ternary Rhenium(I) Complexes: from Fluorescent Reporters to Interesting Scaffolds for Dual-Imaging Heterobimetallic Probes

Five ternary tricarbonylrhenium(I) complexes based on a pyridinetriazole moiety, so called pyta, were synthesized and spectroscopically characterized. The photophysical properties of these cationic complexes of general formula, [Re(CO)3(pyta-COOMe)L] (L = substituted pyridine derivatives) have been investigated, as well. Three of them are fluorescent and could be considered as interesting scaffolds for the preparation of dual-imaging heterobimetallic species

Tetraphenylphosphonium [N-(2-aminophenyl)-2-(mercaptomethylcarbonylamino)ethanamido(4-)-[kappa]4S,N,N',N'']oxorhenate(V)

The title compound, (C24H20P)[Re(C10H9N3O2S)O], contains well separated square-pyramidal [OReL]- complex anions (L is the deprotonated N-(2-aminophenyl)-2-(mercaptomethylcarbonylamino)ethanamide ligand) and tetrahedral [(C6H5)4P]+ cations. In the anion, the Re=O bond is oriented along the apical direction and the four basal sites are occupied by one S- and three N-atom donors of the tetradentate L4- ligand

Різнолігандні комплекси ренію(i): від флуоресцентних міток до гетеробіметалічних зон- дів з цікавою топологією для подвійної візуалізації

In this paper, five new ternary tricarbonylrhenium(I) complexes based on a pyridinetriazole moiety, the so-called pyta, have been investigated. These cationic complexes of the general formula [Re(CO)3(pyta-COOMe)L] (L = substituted pyridine derivatives) combine a carboxylate functionalization, for further biomolecule conjugation, with a metal chelating site – a pyta-based tricarbonylrhenium moiety – which can act as a fluorescent reporter. The complexes have been prepared using a two-steps pathway involved the activation of [Re(CO)3Cl(bipy)] with triflate silver salts in the presence of acetonitrile followed by the thermally activated substitution of the acetonitrile adduct by commercially available substituted pyridine derivatives. They have been prepared from modest to good yields, fully characterized by means of NMR, IR and mass spectrometry, and their photophysical properties have been investigated. Upon excitation into the MLCT band of each complex (absorption band at ca. 300 nm), three of them exhibit a bright green luminescence centered at c.a. 494 nm, with a quantum yield of 0.60% in acetonitrile. These interesting photophysical features make them potential fluorescent cellular imaging agents. Moreover, thank to their ancillary ligand, they could be also considered as interesting scaffolds for the preparation of dual-imaging heterobimetallic species.В данной работе представлены результаты исследований пяти новых разнолигандных трис-карбонильных комплексов рения(I) на основе пиридинтриазольных производных, так называемых pyta. Такие катионные комплексы общей формулы [Re(CO)3(pyta-COOMe)L] (L = производные пиридина) сочетают в себе карбоксилатную функциональную группу для дальнейшего биомолекулярного связывания с хелатированным металлсодержащим фрагментом – на основе pyta-трискарбонильных комплексных частиц, которые могут выступать в качестве флуоресцентного центра. Комплексы были получены двухстадийной реакцией, основанной на активации [Re(CO)3Cl(bipy)] трифлатом серебра в присутствии ацетонитрила с дальнейшим взаимодействием термически активированного ацетонитрильного аддукта с коммерчески доступными замещенными пиридинпроизводными. Координационные соединения были получены с разными выходами, исследованы методами ЯМР-, ИК- и масс-спектроскопии и изучены их фотофизические свойства. При использовании длины волны возбуждения, соответствующей центру полосы переноса заряда металл-лиганд (MLCT) для каждого комплекса (полоса поглощения ~ 300 нм), три из них проявляют ярко-зеленую люминесценцию в ацетонитриле с центром ~ 494 нм и квантовым выходом 0,60%. Такие фотофизические особенности делают их потенциальными флуоресцентными биовизуализирующими агентами. Кроме того, благодаря дополнительным лигандам они могут быть использованы как основа для получения гетеробиметаллических частиц для двойственной визуализации.В даній публікації представлені результати досліджень п’яти нових різнолігандних трис-карбонільних комплексів ренію(I) на основі піридинтриазольних похідних, так званих pyta. Такі катіонні комплекси загальної формули [Re(CO)3(pyta-COOMe)L] (L = похідні піридину) поєднують карбоксилатну функціональну групу, яка може бути використана для подальшого біомолекулярного зв’язування з хелатованим металовмісним фрагментом на основі pyta-трис-карбонільних комплексних часточок, які можуть виступати в якості флуоресцентного центру. Комплекси були отримані двостадійною реакцією, заснованою на активації [Re(CO)3Cl(bipy)] трифлатом срібла в присутності ацетонітрилу з подальшою взаємодією термічно активованого ацетонітрильного аддукту з комерційно доступними заміщеними піридинпохідними. Координаційні сполуки були отримані з різними виходами, охарактеризовані методами ЯМР-, ІЧ- та мас-спектроскопії і досліджені їх фотофізичні властивості. При використанні довжини хвилі збудження, яка відповідає центру смуги переносу заряду метал-ліганд (MLCT) для кожного комплексу (смуга поглинання ~300 нм), три з них виявляють яскраво-червону люмінесценцію в ацетонітрилі з центром ~494 нм та квантовим виходом 0,60%. Такі фотофізичні особливості роблять їх потенційними флуоресцентними біовізуалізуючими агентами. До того ж, завдяки додатковим лігандам вони можуть бути використані як основа для створення гетеробіметалічних часточок для подвійної візуалізації

Cytokine Requirements for Acute and Basal Homeostatic Proliferation of Naive and Memory CD8+ T Cells

Both naive and memory T cells undergo antigen-independent proliferation after transfer into a T cell–depleted environment (acute homeostatic proliferation), whereas only memory T cells slowly divide in a full T cell compartment (basal proliferation). We show, first, that naive and memory CD8+ T cells have different cytokine requirements for acute homeostatic proliferation. Interleukin (IL)-7 receptor(R)α–mediated signals were obligatory for proliferation of naive T cells in lymphopenic hosts, whereas IL-15 did not influence their division. Memory T cells, on the other hand, could use either IL-7Rα– or IL-15–mediated signals for acute homeostatic proliferation: their proliferation was delayed when either IL-7Rα was blocked or IL-15 removed, but only when both signals were absent was proliferation ablated. Second, the cytokine requirements for basal and acute homeostatic proliferation of CD8+ memory T cells differ, as basal division of memory T cells was blocked completely in IL-15–deficient hosts. These data suggest a possible mechanism for the dearth of memory CD8+ T cells in IL-15– and IL-15Rα–deficient mice is their impaired basal proliferation. Our results show that naive and memory T lymphocytes differ in their cytokine dependence for acute homeostatic proliferation and that memory T lymphocytes have distinct requirements for proliferation in full versus empty compartments

Association of Bevacizumab Plus Oxaliplatin-Based Chemotherapy With Disease-Free Survival and Overall Survival in Patients With Stage II Colon Cancer A Secondary Analysis of the AVANT Trial

IMPORTANCE: In the pivotal Bevacizumab-Avastin Adjuvant (AVANT) trial, patients with high-risk stage II colon cancer (CC) had 5-year and 10-year overall survival (OS) rates of 88% and 75%, respectively, with adjuvant fluorouracil and oxaliplatin-based chemotherapy; however, the trial did not demonstrate a disease-free survival (DFS) benefit of adding bevacizumab to oxaliplatin-based chemotherapy in stage III CC and suggested a detrimental effect on OS. The Long-term Survival AVANT (S-AVANT) study was designed to collect extended follow-up for patients in the AVANT trial. OBJECTIVE: To explore the efficacy of adjuvant bevacizumab combined with oxaliplatin-based chemotherapy in patients with high-risk, stage II CC. DESIGN, SETTING, AND PARTICIPANTS: This prespecified secondary end point analysis of the AVANT and S-AVANT studies included 573 patients with curatively resected high-risk stage II CC and at least 1 of the following criteria: stage T4, bowel obstruction or perforation, blood and/or lymphatic vascular invasion and/or perineural invasion, age younger than 50 years, or fewer than 12 nodes analyzed. The AVANT study was a multicenter randomized stage 3 clinical trial. Data were collected from December 2004 to February 2019, and data for this study were analyzed from March to September 2019. INTERVENTION: Patients were randomly assigned to receive 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX4), FOLFOX4 with bevacizumab, or capecitabine and oxaliplatin (XELOX) with bevacizumab. MAIN OUTCOMES AND MEASURES The primary end points of this secondary analysis were DFS and OS in patients with high-risk stage II CC. RESULTS The AVANT study included 3451 patients, of whom 573 (16.6%) had high-risk stage II CC (192 [33.5%] randomized to FOLFOX4 group; 194 [33.9%] randomized to FOLFOX4 with bevacizumab group; 187 [32.6%] randomized to XELOX with bevacizumab group). With a median (interquartile range) age of 57.0 (47.2-65.7) years, the study population comprised 325 men (56.7%) and 248 women (43.3%). After a median (interquartile range) follow-up of 6.9 (6.1-11.3) years, the 3-year DFS and 5-year OS rates were 88.2% (95% CI, 83.7%-93.0%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 group, 86.6% (95% CI, 81.8%-91.6%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 with bevacizumab group, and 86.7% (95% CI, 81.8%-91.8%) and 93.2% (95% CI, 89.6%-97.0%) in the XELOX with bevacizumab group, respectively. The DFS hazard ratio was 0.94 (95% CI, 0.59-1.48; P = .78) for FOLFOX4 with bevacizumab vs FOLFOX4 and 1.07 (95% CI, 0.69-1.67; P = .76) for XELOX with bevacizumab vs FOLFOX4. The OS hazard ratio was 0.92 (95% CI, 0.55-1.55; P = .76) for FOLFOX4 with bevacizumab vs FOLFOX4 and 0.85 (95% CI, 0.50-1.44; P = .55) for XELOX with bevacizumab vs FOLFOX4. CONCLUSIONS AND RELEVANCE: In this secondary analysis of data from the AVANT trial, adding bevacizumab to oxaliplatin-based chemotherapy was not associated with longer DFS or OS in patients with high-risk stage II CC. The findings suggest that the definition of high-risk stage II CC needs to be revisited