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The presence of positron emission tomography (PET) centers at most major hospitals worldwide, along with the improvement of PET scanner sensitivity and the introduction of total body PET systems, has increased the interest in the PET tracer development using the short-lived radionuclides carbon-11. In the last few decades, methodological improvements and fully automated modules have allowed the development of carbon-11 tracers for clinical use. Radiolabeling natural compounds with carbon-11 by substituting one of the backbone carbons with the radionuclide has provided important information on the biochemistry of the authentic compounds and increased the understanding of their

The fac-[M(CO)3(PyA)(P)] and cis-trans-[M(CO)2(PyA)(P)2] neutral complexes (M is Re or 99mTc), based on the mixed ligand strategy with pyrazine-2-carboxylic acid (PyAH) as the bidentate N,O and triphenylphosphine as the monodentate P ligand, are presented. Through the employment of the anhydride of pyrazine-2,3-dicarboxylic acid (PyDA), the PyAH scaffold was conveniently derivatized with the model bioactive amine 1-(2-methoxyphenyl)piperazine, the active part of the 5-HT1A antagonist WAY100635. Reaction of either PyAH or the pharmacophore-bearing PyAH ligand (L1H) with fac-[M(CO)3]+ core in water yielded the intermediate fac-[M(CO)3(PyA)(H2O)] complexes. The labile aqua ligand was easily replaced by PPh3 to yield the fac-[Re(CO)3(PyA)(PPh3)] complexes, while in toluene under reflux, the cis-trans-[Re(CO)2(PyA)(PPh3)2] complexes were obtained. The latter complexes were alternatively obtained from mer-[Re(CO)3(PPh3)2Cl] by refluxing with the PyA ligand in toluene. The analogous 99mTc complexes were synthesized quantitatively, showing excellent stability in competition studies. The methodology described herein represents a practical procedure for the effective integration of the fac-[M(CO)3]+ core with amine-bearing biologically active compounds for diagnosis/therapy.

Epidermal growth factor receptors (EGFR) of tyrosine kinase (TK) have shown high expression levels in most cancers and are considered a promising target for cancer diagnosis and therapy. Expanding the investigation for novel targeted radiopharmaceuticals, an EGFR inhibitor such as 4-aminoquinazoline derivatives along with a radionuclide such as technetium-99m (99mTc) could be ideal. Thus, we report herein the synthesis, characterization, and biological evaluation of new “4 + 1” mixed-ligand ReIII- and 99mTcIII-complexes of the general formula [99mTc][Tc(NS3)(CN-R)] bearing tris(2-mercaptoethyl)-amine (NS3) as the tetradentate tripodal ligand and a series of isocyanide derivatives (CN-R) of tyrosine kinase inhibitor (3-bromophenyl)quinazoline-4,6-diamine as the monodentate ligand. The quinazoline isocyanide derivatives 4a-d were prepared in two steps and reacted with the [Re(NS3)PMe2Ph] precursor leading to the final complexes 5a-d in high yield. All compounds were characterized by elemental analysis, IR, and NMR spectroscopies. In vitro studies, for their potency to inhibit the cell growth, using intact A431 cells indicate that the quinazoline derivatives 4a-d and the Re complexes 5a-d significantly inhibit the A431 cell growth. In addition, the EGFR autophosphorylation study of complex 5b shows an IC50 value in the nanomolar range. The corresponding “4 + 1” 99mTc-complexes 6a-d were prepared by employing the [99mTc]TcEDTA intermediate and the appropriate monodentate 4a-d in a two-step synthetic procedure with a radiochemical yield (RCY) from 63 to 77 % and a radiochemical purity (RCP) > 99 % after HPLC purification. Their structures have been established by HPLC comparative studies using the well-characterized Re-complexes 5a-d as reference. All 99mTc-complexes remain stable for at least 6 h, and their logD7.4 values confirmed their anticipated lipophilic character. Biodistribution studies in healthy Swiss albino mice of 99mTc-complexes showed hepatobiliary excretion and initial fast blood clearance. Complex 6b was also tested in Albino SCID mice bearing A431 tumors and showed rapid tumor uptake at 5 min (2.80 % ID/g) with a moderate tumor/muscle ratio (2.06) at 4 h p.i. The results encourage further investigation for this type of 99mTc-complexes as single-photon emission computed tomography (SPECT) radio agents for imaging tumors overexpressing EGFR. © 2022 Elsevier Ltd

We report herein the preclinical evaluation of new [64Cu]Cu-gastrin-releasing peptide receptor (GRPR)-targeting tracers, employing the potent peptide antagonist DPhe-Gln-Trp-Ala-VaI-Gly-His-Sta-Leu-NH2 conjugated to NOTA (in 1) or NODAGA (in 2) chelators via a 6-aminohexanoic acid linker. The Cu-1/2 metalated peptides were synthesized by reacting 1/2 with CuCl2 and were characterized by LC-ESI-MS and HR-ESI-MS. Cu-1/2 exhibited high GRPR-binding affinities with IC50 values

The

The growing fatigue of citizens due to the COVID-19 pandemic has already been addressed and its results are visible and threatens citizen compliance. The aim of this study was to translate and validate the Pandemic Fatigue Scale (PFS) in the Greek language. A cross-sectional study was conducted between October 2021 to March 2022. The translation and cultural adaptation process was developed according to the research protocols among the university student population in Cyprus and tested the psychometric properties of PFS. Three hundred thirty-four subjects participated in the study through a web survey, which included general information and the study process. The internal consistency for the total PFS showed good reliability (six items, a = 0.88). A weak statistically significant positive correlation was found between the PFS and the Greek versions of Generalised Anxiety Disorder Assessment—GAD-7 (r = 0.1.96; p < 0.001) and the PFS and Patient Health Questionnaire—PHQ-9 (r = 0.173; p = 0.002) demonstrating good concurrent validity. Recovering from the pandemic, it is necessary to build systems to detect and respond to future healthcare crises. The results suggest that the psychometric properties of the Greek PFS are satisfactory. The measure of pandemic fatigue allows for identifying fatigue groups for targeted interventions and testing how pandemic fatigue might be reduced in such situations.

A series of "2 + 1" mixed ligand tricarbonyl complexes of the general formula fac-[Re/

We report herein the preclinical evaluation of new [

The synthesis and evaluation of three novel 99mTc complexes (99mTc-1–3) and their corresponding Re complexes (Re-1–3), in which the phenyl ring of 2-phenylbenzothiazole or 2-phenylbenzimidazole is replaced by the cyclopentadienyl tricarbonyl [Cp99mTc(CO)3] core, are reported. Both 99mTc and Re complexes were prepared from the corresponding ferrocenyl derivatives, and the Re complexes were fully characterized by elemental analysis, spectroscopic methods, and X-ray crystallography. The complexes exhibit effective in vitro binding to β-amyloid (Aβ) plaques and fibrils, inhibit Aβ fibril formation, and significantly reduce Aβ-induced cytotoxicity and reactive oxygen species production in neuronal cell cultures. The brain uptake of the 99mTc complexes ranges between 7.94 and 3.99% ID/g at 2 min p.i., being the highest recorded for potential 99mTc Aβ plaque imaging probes in mice. Powered by their high brain uptake, the complexes represent strong theranostic candidates against Alzheimer’s disease combining sing...

The synthesis and characterization of the dicarbonyl mixed ligand cis-[Re(CO)2(quin)(cisc)(PPh3)] complex, 4, where quin is the deprotonated quinaldic acid, cisc is cyclohexyl isocyanide, and PPh3 is triphenylphosphine, is presented. The synthesis of 4 proceeds in three steps. In the first, the intermediate fac-[Re(CO)3(quin)(H2O)] aqua complex 2 is generated from the fac-[NEt4]2[Re(CO)3Br3] precursor, together with the brominated products fac-[Re(CO)3(quinH)(Br)] 1a and fac-[NEt4][Re(CO)3(quin)(Br)] 1b, in low yield. In the following step, replacement of the aqua ligand of complex 2 by the monodentate isocyanide ligand leads to the formation of fac-[Re(CO)3(quin)(cisc)], 3. In the third step replacement of the species trans to the isocyanide carbonyl group of 3 by a phosphine generates complex 4. The Re complexes 2–4 were prepared in high yield and fully characterized by elemental analysis, spectroscopic methods, and X-ray crystallography. At the technetium-99m (99mTc) tracer level, the analogous complex...

Introduction Lipophilic delocalized cations accumulate in tumor cell mitochondria due to their higher transmembrane potential. In this work, this strategy was adopted for the development of 99m Tc tumor-targeted imaging agents. Methods Two tridentate ligands containing the triphenylphosphonium cation, L1 (S-cysteinyl) and L2 (N-iminodiacetate) as well as the respective 99m Tc/ReL1 and 99m Tc/ReL2 tricarbonyl complexes were synthesized. The effect of the ligands and the Re complexes on cell growth in U-87 MG glioblastoma cells was assessed. In vitro stability studies and measurement of logP of the 99m Tc tracers was performed. The cellular and mitochondrial uptake of the 99m Tc tracers in U-87 MG cells was evaluated. Biodistribution of 99m TcL1 and 99m TcL2 were performed on SCID mice bearing U-87 MG tumors. Results The ligands L1 , L2 and the Re1 and ReL2 complexes were characterized spectroscopically. Single products 99m TcL1 and 99m TcL2 , >90% stable in rat serum, were obtained. LogP was 0.40±0.14 for 99m TcL1 and −0.02±0.07 for 99m TcL2 . L1 , ReL1 and ReL2 caused no notable cytotoxicity and L2 was found to infer 40% inhibition of cellular growth at 10 −5 M as well as 80% cell death in culture at 10 −4 M. The cell uptake of 99m TcL1 and 99m TcL2 over 4h was 1.26±0.08% and 0.06±0.01% respectively, of which 13.41±3.63% and 18.61±6.19% was distributed in the mitochondria respectively. The initial tumor uptake in mice was found to be >1% ID/g for both 99m Tc tracers. Conclusions In vitro mitochondrial and in vivo tumor targeting was observed, better in 99m TcL1 , however these properties should be optimized in future studies. Advances in Knowledge and Implications for Patient Care: Continuous efforts in this direction may lead to a suitable mitochondrial-targeted 99m Tc imaging agent for tumor detection.

A series of “2 + 1” mixed ligand tricarbonyl complexes of the general formula fac-[Re/99mTc/186Re(CO)3(DDTC)(L)] containing diethyldithiocarbamate (DDTC) as a monoanionic bidentate ligand and a series of monodentate ligands L was synthesized, characterized and evaluated. The impact of ligand L on the radiochemical yield (RCY) and biodistribution of the final compounds was also investigated. DDTC and the appropriate L ligand [cyclohexyl isocyanide (cisc), tert-butyl isocyanide (tbi), triphenylphosphine (PPh3), methyldiphenylphosphine (PPh2Me), triphenylarsine (AsPh3), imidazole (im), and 4-aminopyridine (4AP)] readily reacted in equimolar amounts with the [Et4N]2[Re(CO)3Br3] precursor to afford fac-[Re(CO)3(DDTC)(cisc)], Re1, fac-[Re(CO)3(DDTC)(tbi)], Re2, fac-[Re(CO)3(DDTC)(PPh3)], Re3, fac-[Re(CO)3(DDTC)(PPh2Me)], Re4, fac-[Re(CO)3(DDTC)(AsPh3)], Re5, fac-[Re(CO)3(DDTC)(im)], Re6 and fac-[Re(CO)3(DDTC)(4AP)], Re7, complexes in high yields (>80%). All Re complexes were fully characterized by IR, NMR, and in addition Re4, Re5, and Re7 with X-ray crystallography. Analogous reactions as performed with Re were subsequently explored on the 99mTc and 186Re-tracer levels using the corresponding fac-[99mTc/186Re(CO)3(H2O)3]+ precursor. Complexes 99mTc1 – 99mTc5, 186Re1 and 186Re3 were obtained in high radiochemical yield (>91%), while the complexes 99mTc6, 99mTc7 and 186Re7 formed with radiochemical yields of 55%, 28%, and 75%, respectively. The 99mTc and 186Re-complexes were characterized by comparative HPLC analysis using the analogous Re complexes. During histidine and cysteine challenge experiments at 37 °C through 6 h, complexes 99mTc1 – 99mTc5 remained > 92% stable, while complexes 99mTc6 and 99mTc7 remained only 8% stable through 3 h. Similar studies for 186Re-complexes showed that 186Re1 and 186Re3 remained > 95% stable for up to 48 h, while 186Re7 had decreased to 7% after 3 h. LogD7.4 data of 99mTc1 – 99mTc5, 186Re1, and 186Re3 complexes, which ranged from 2.59 to 3.39, suggested high lipophilicity. Biodistribution studies in healthy Swiss albino mice showed hepatobiliary excretion for 99mTc1, 99mTc2, and 99mTc4, fast blood clearance for 99mTc4, while high liver uptake and retention for 99mTc3 and 99mTc5 were measured. Moreover, 99mTc2 showed high accumulation in the lungs with sustained retention (52.80% ID/g at 4 h p.i.) and significant brain uptake at 2 min p.i. (1.89% ID/g). The study showed the great influence of monodentate ligand in the synthesis and biodistribution of the mixed ligand complexes.

Tyrosine kinase (TK) receptors including epidermal growth factor receptors (EGFRs) are known to be overexpressed in a wide variety of solid tumors associated with poor prognosis. The HBED-CC chelator N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid 1 was coupled via one or both its propionic acid moieties with the quinazoline EGFR-TK inhibiting pharmacophore 4-amino-N-(4-((3-bromophenyl)amino)quinazolin-6-yl)butanamide 3 resulting in either a monomeric 4 or a dimeric 5 species. Ligands 4 and 5 reacted with Ga

The ReI atom in the mol­ecule of the title compound has a distorted C4NO coordination sphere defined by three carbonyl ligands, one chelating quinaldate anion and one isocyanide ligand. As a result of the trans effect of the isocyanide derivative, one Re—CO bond is elongated., In the title compound, [Re(C10H6NO2)(C7H11N)(CO)3], the ReI atom is coordinated by three carbonyl ligands in a facial arrangement and by the N, O and C atoms from a chelating quinaldate anion and a monodentate isocyanide ligand, respectively. The resultant C4NO coordination sphere is distorted octa­hedral. A lengthening of the axial Re—CO bond trans to the isocyanide ligand is indicative of the trans effect. Individual complexes are stacked into rods parallel to [001] through displaced π–π inter­actions. Weak C—H⋯O hydrogen-bonding inter­actions between the rods lead to the formation of layers parallel to (010). These layers are stacked along [010] by C—H⋯H—C van der Waals contacts.

Tyrosine kinase (TK) receptors including epidermal growth factor receptors (EGFRs) are known to be overexpressed in a wide variety of solid tumors associated with poor prognosis. The HBED-CC chelator N,N′-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N′-diacetic acid 1 was coupled via one or both its propionic acid moieties with the quinazoline EGFR-TK inhibiting pharmacophore 4-amino-N-(4-((3-bromophenyl)amino)quinazolin-6-yl)butanamide 3 resulting in either a monomeric 4 or a dimeric 5 species. Ligands 4 and 5 reacted with Ga3+ generating the corresponding complexes Ga4 and Ga5. Both ligands and complexes were characterized with mass spectrometry and NMR spectroscopy and evaluated in vitro with MTT assays in A431 cells, where they showed IC50 values in the range 51.6 to 68.8 μM. Labeling of ligands 4 and 5 with the PET radionuclide 68Ga was quantitative and resulted in tracers [68Ga]Ga4 and [68Ga]Ga5 with radiochemical purities greater than 98%, which were also characterised by comparative RP-HPLC studies with Ga4 and Ga5 respectively. Radiotracers [68Ga]Ga4 and [68Ga]Ga5 were stable (intact tracer over 98%) in the reaction mixture (120 min) and in human serum (30 min). Both tracers were evaluated in vivo with biodistribution experiments in SCID mice bearing A431 tumors presenting tumor uptake of 1.34 for [68Ga]Ga4 and 1.01 %ID/g for [68Ga]Ga5 at 5 min, which was slightly decreased at 60 min p.i. and then remained stable until 120 min p.i. To the best of our knowledge, this is the first report of monomeric and dimeric quinazoline conjugates with the chelator HBED-CC, which can serve as a basis for further development of EGFR-TKI targeting tracers.

The synthesis and evaluation of three novel

The synthesis and characterization of the dicarbonyl mixed ligand cis-[Re(CO)

New neutral fac-ReNNN(CO)3 complexes where NNN are the Schiff base tridentate ligands N-(1H-pyrrol-2-ylmethylene)-2-(pyridin-2-yl)ethanamine (complex 1) and N-(1H-indol-2-ylmethylene)-2-(pyridin-2-yl)ethanamine (complex 2) were synthesized and characterized by elemental analyses, infrared and 1H and 13C NMR spectroscopies. The molecular structure of complex 1 was confirmed by X-ray crystallographic analysis that revealed a distorted octahedral geometry around Re.

Lipophilic delocalized cations accumulate in tumor cell mitochondria due to their higher transmembrane potential. In this work, this strategy was adopted for the development ofTwo tridentate ligands containing the triphenylphosphonium cation, L1 (S-cysteinyl) and L2 (N-iminodiacetate) as well as the respectiveThe ligands L1, L2 and the Re1 and ReL2 complexes were characterized spectroscopically. Single productsIn vitro mitochondrial and in vivo tumor targeting was observed, better in

The development of a 99mTc-radiotracer for imaging of β-amyloid (Aβ) plaques with single photon emission computed tomography (SPECT) is strongly anticipated to provide a low cost and broadly accessible diagnostic tool for Alzheimer’s disease (AD). Within this framework, 2-(4′-aminophenyl)benzothiazole, known to display affinity and specificity for Aβ plaques, has been joined to the tricarbonyl fac-[M(CO)3]+ (M = Re(I), 99mTc(I)) core through the cyclopentadienyl moiety to yield stable, neutral, and lipophilic complexes (Re-1 and 99mTc-1, respectively). The Re-1 complex was completely characterized with spectroscopic methods and was shown to selectively stain Aβ plaques on sections of human AD brain tissue. The 99mTc-1 complex displayed satisfactory initial brain uptake (0.53% ID/g at 2 min) and in vivo stability in healthy mice, while in transgenic 5xFAD mice, models for AD, a notable retention in the brain was noted (1.94% ID/g at 90 min). The results are encouraging and contribute to the effort of devel...

In the present work, we investigated potential means to obtain neutral tricarbonyl mixed-ligand fac-[M(CO)(3)(LL2)-L-1] complexes (M = Re, Tc-99m) containing the (2-hydroxyphenyl)diphenylphosphine (POH) bidentate ligand ((LH)-H-1) and a series of monodentate ligands (L-2). First, fac[Re(CO)(3)(PO)(H2O)], 1, was synthesized by reaction of POH and [Et4N](2)[Re(CO)(3)Br-3] in equimolar amounts in MeOH at room temperature. Interestingly, with excess of POH this reaction afforded fac-[Re(CO)(3)(PO)(POH)], 2, with POH operating both as a bidentate and as a monodentate ligand. Owing to the presence of the labile aqua ligand, which can be readily replaced by various monodentate ligands, 1 was further used as a precursor to generate a small library of the desired fac-[M(CO)(3)(LL2)-L-1] complexes. Specifically, by reaction of triphenylphosphine (PPh3), imidazole (im), pyridine (py), cyclohexyl isocyanide (cisc), and tert-butyl isocyanide (tbi), the following products were readily obtained in excellent yields (92%-95%): fac-[Re(CO)(3)(PO)(PPh3)], 3, fac-[Re(CO)(3)(PO)(im)], 4, fac-[Re(CO)(3)(PO)(py)], 5, fac-[Re(CO)(3)(PO)(CiSc)], 6, and fac-[Re(CO)(3)(PO)(tbi)], 7. All compounds were fully characterized by elemental analysis, IR and NMR spectroscopies, and electrospray ionization(+) mass spectrometry. Their solid-state structure was elucidated by X-ray crystallography. Of considerable interest is the fact that the corresponding 2'-7' were easily accessible at the Tc-99m-tracer level in quantitative yields after reaction of POH and the respective monodentate ligand L-2 with fac-[Tc-99m(CO)(3)(H2O)(3)] in aqueous MeOH, as verified by comparative chromatographic methods adopting dual photo and radiometric detection modes. The high stability displayed by all Tc-99m complexes during histidine and cysteine challenge assays underscored the suitability of the fac-[M(CO)(3)(PO)L-2] system for radiopharmaceutical development purposes.

In the title rhenium(I) tricarbonyl complex with tri­phenyl­arsane and deprotonated quinaldic acid ligands, the ReI atom is in an octa­hedral coordination. Weak C—H⋯O inter­actions lead to a three-dimensional supra­molecular architecture., In the title compound, [Re(C10H6NO2)(CO)3{As(C6H5)3}], the coordination environment of ReI is that of a distorted octa­hedron. Three coordination sites are occupied by three carbonyl groups in a facial arrangement and the remaining three sites by tri­phenyl­arsane and deprotonated quinaldic acid in As-mono- and N,O-bidentate fashions, respectively. In the crystal, the complexes are linked through weak C—H⋯O hydrogen bonds, forming a three-dimensional network. It worth noting that, as far as we know, this complex is the first ReI tri­phenyl­arsane tricarbonyl compound to be reported.

mixed ligand fac-[Re(PO)(P)(CO)3] complex, 2, where POH acts as both a bidentate and amonodentate ligand. Complex 1 is practically a precursor owing to the presence of the labile water molecule which can be readily replaced by a variety of biologically relevant monodentate ligands. Both complexes have been fully characterized in the solid and solution states by elemental analysis, IR and NMR spectroscopies, and ESI(+)-mass spectrometry. Their solid-state structure has been elucidated by X-ray crystallography. These results were successfully translated at the Tc-tracer level using the fac-[Tc(H2O)3(CO)3] complex as precursor. The respective Tc(I) complexes were characterized by comparative HPLC studies after co-injection with the authentic Re-complexes and comparison of elution times.