Metals of interest for biomedical applications often need to be complexed and associated in a stable manner with a targeting agent before use. Whereas the fundamentals of most transition‐metal ...complexation processes have been thoroughly studied, the complexation of ZrIV has been somewhat neglected. This metal has received growing attention in recent years, especially in nuclear medicine, with the use of 89Zr, which a β+‐emitter with near ideal characteristics for cancer imaging. However, the best chelating agent known for this radionuclide is the trishydroxamate desferrioxamine B (DFB), the ZrIV complex of which exhibits suboptimal stability, resulting in the progressive release of 89Zr in vivo. Based on a recent report demonstrating the higher thermodynamic stability of the tetrahydroxamate complexes of ZrIV compared with the trishydroxamate complexes analogues to DFB, we designed a series of tetrahydroxamic acids of varying geometries for improved complexation of this metal. Three macrocycles differing in their cavity size (28 to 36‐membered rings) were synthesized by using a ring‐closing metathesis strategy, as well as their acyclic analogues. A solution study with 89Zr showed the complexation to be more effective with increasing cavity size. Evaluation of the kinetic inertness of these new complexes in ethylenediaminetetraacetic acid (EDTA) solution showed significantly improved stabilities of the larger chelates compared with 89Zr‐DFB, whereas the smaller complexes suffered from insufficient stabilities. These results were rationalized by a quantum chemical study. The lower stability of the smaller chelates was attributed to ring strain, whereas the better stability of the larger cyclic complexes was explained by the macrocyclic effect and by the structural rigidity. Overall, these new chelating agents open new perspectives for the safe and efficient use of 89Zr in nuclear imaging, with the best chelators providing dramatically improved stabilities compared with the reference DFB.
Perfect package: A series of cyclic and acyclic hydroxamic acid based chelators was designed to provide ZrIV complexes with optimal kinetic inertness (see figure). Their evaluation showed that the chelators with the best preorganization provided significantly superior stabilities than desferrioxamine B, the reference compound used in nuclear imaging with 89Zr. The results are rationalized with quantum chemical calculations.
Aryliodonium salts have become precursors of choice for the synthesis of 18F‐labeled tracers for nuclear imaging. However, little is known on the reactivity of these compounds with heavy halides, ...that is, radioiodide and astatide, at the radiotracer scale. In the first comparative study of radiohalogenation of aryliodonium salts with 125I− and 211At−, initial experiments on a model compound highlight the higher reactivity of astatide compared to iodide, which could not be anticipated from the trends previously observed within the halogen series. Kinetic studies indicate a significant difference in activation energy (Ea=23.5 and 17.1 kcal mol−1 with 125I− and 211At−, respectively). Quantum chemical calculations suggest that astatination occurs via the monomeric form of an iodonium complex whereas iodination occurs via a heterodimeric iodonium intermediate. The good to excellent regioselectivity of halogenation and high yields achieved with diversely substituted aryliodonium salts indicate that this class of compounds is a promising alternative to the stannane chemistry currently used for heavy radiohalogen labeling of tracers in nuclear medicine.
Wherever I lay my At: Radiohalogenation of diaryiodonium salts has been investigated and a significantly higher reactivity of astatide has been observed. Regioselectivity and reaction kinetics can be controlled by varying the nature of substituents. The high reactivity of these precursors makes them an attractive alternative to the conventional arylstannane chemistry for radiolabeling with iodine and astatine.
DOTA (1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid)‐based chelates that give only a single isomer in solution when complexed with lanthanide (Ln3+) ions is of value for studying protein ...dynamics and interactions via NMR. Herein, we have investigated the geometries, energetics, and electrostatic potentials of Lu complexed with DOTA (1), ring methylated M4DOTA (2), and arm methylated R‐DOTMA (3) and S‐DOTMA (4), as well as, both ring and arm methylated 4S‐4S‐M4DOTMA (5) and 4S‐4R‐M4DOTMA (6) at the level of M06‐L/6‐31+G(d)‐SDD, to elucidate the origin of the isomer stability. These analyses indicate that the electrostatic repulsion between the arm methyl and the neighboring carboxylate significantly destabilizes the square antiprism (SAP) isomer of Lu‐5 and the twisted square antiprism (TSAP) isomer of Lu‐6, while the steric repulsion between the ring and arm methyl groups attenuates the stability of both TSAP of Lu‐5 and SAP of Lu‐6. To rationalize the variable temperature proton NMR spectra, the energy barriers for the inter‐conversion in Lu‐5 and Lu‐6 via arm rotation were also calculated. The modulation of the stability and rigidity of Ln complexes via a modification of DOTA is also discussed. Our investigation will aid to design better chelates for the Ln3+ ions for its use in molecular medicine.
The geometries, energetics, and electrostatic potentials of Lu complexed with the polymethylated 4S‐4S‐M4DOTMA (5) and 4S‐4R‐M4DOTMA (6) were investigated with DFT to elucidate the origin of the isomer stability. The modulation of the stability and rigidity of Ln complexes is also discussed with the aim of designing better chelates for the Ln3+ ions for its use in molecular medicine.
The radiofluorination of diaryliodonium salts is of value for producing radiotracers for positron emission tomography. We report crystal structures for two diaryliodonium fluorides. Whereas ...diphenyliodonium fluoride (1 a) exists as a tetramer bridged by four fluoride ions, 2‐methylphenyl(phenyl)iodonium fluoride (2 a) forms a fluoride‐bridged dimer that is further halogen bonded to two other monomers. We discuss the topological relationships between the two and their implications for fluorination in solution. Both radiofluorination and NMR spectroscopy show that thermolysis of 2 a gives 2‐fluorotoluene and fluorobenzene in a 2 to 1 ratio that is in good agreement with the ratio observed from the radiofluorination of 2‐methylphenyl(phenyl)iodonium chloride (2 b). The constancy of the product ratio affirms that the fluorinations occur via the same two rapidly interconverting transition states whose energy difference dictates chemoselectivity. From quantum chemical studies with density functional theory we attribute the “ortho‐effect” to the favorable electrostatic interaction between the incoming fluoride and the o‐methyl in the transition state. By utilizing the crystal structures of 1 a and 2 a, the mechanisms of fluoroarene formation from diaryliodonium fluorides in their monomeric, homodimeric, heterodimeric, and tetrameric states were also investigated. We propose that oligomerization energy dictates whether the fluorination occurs through a monomeric or an oligomeric pathway.
Origin of the ortho effect: The “ortho effect” imparted by an o‐alkyl group in the reaction of diaryliodonium salts with a fluoride ion is attributed to a favorable electrostatic interaction between the incoming fluoride and the o‐methyl group in the transition state (TSB).
A rigidified and symmetrical polymethylated 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) ligand bearing four SSSS methyl groups in both the tetraaza ring and the acetate arms ...(SSSS-SSSS-M4DOTMA) was prepared. The isomer ratio of SSSS-SSSS-M4DOTMA complexed with a series of lanthanide ions was carefully investigated using RP-HPLC and NMR. A square antiprismatic (SAP) configuration was exclusively observed for the early lanthanides, while the twisted square antiprismatic (TSAP) geometry was preferred as the lanthanide ion size decreases. The late lanthanides preferentially adopted the TSAP geometry. One of the pendant arms was modified with a pyridyl disulfide group (SSSS-SSSS-M8SPy) for cysteine attachment and displayed a similar isomer trend as the parent compound, Ln-SSSS-SSSS-M4DOTMA. Covalent attachment to the ubiquitin S57C mutant showed resonances whose intensities are in agreement with the isomeric population observed by RP-HPLC. Furthermore, the NOE experiments combined with quantum chemical calculations have unequivocally demonstrated that the SAP of Pr-SSSS-SSSS-M4DOTMA and Pr-SSSS-SSSS-M8SPy, as well as the TSAP of Yb-SSSS-SSSS-M8SPy are more stable than their corresponding isomers.
Automated guided vehicle systems (AGVSs) are used to transport goods and products in most manufacturing systems. In this research, we use a cylindrical magnet spot, which is widely used in industrial ...AGVSs, to develop a guidance system for indoor AGV navigation. This paper describes the navigation and control system of an AGV by magnet spot guidance with a differential drive. Furthermore, Hall-effect sensors, encoders, and counters are employed to achieve control and continuous guidance. Existing guidance methods use a gyro sensor and dead reckoning with encoders to calibrate against steering angle errors. Here, the maximum value of the magnetic flux density of the magnet spot, which is obtained by the Hall-effect sensor, is used to calibrate against steering angle errors and as a navigation guide for the AGV. Furthermore, real-time corrections for wheel-skidding errors are accomplished with a fuzzy controller. Thus, high-precision continuous guidance with stable and satisfactory navigation at high speeds is achieved. This guidance method was applied to real manufacturing processes in a ceramic plant and steel-bar reinforcement plant to examine its control ability, stability, and effectiveness. The proposed method was found to be robust to disturbances and uncertainty problems during tracking.
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► We report a guidance method for AGVSs using cylindrical magnet spot and differential drive. ► Hall-effect sensors, encoders, and counters have been used for control and continuous guidance. ► Maximum value of magnetic flux density of the magnet spot is used to calibrate against steering angle errors. ► High-precision continuous guidance with stable and satisfactory navigation at high speeds is achieved. ► This method was found to be robust to disturbances and uncertainty problems during tracking.
Low serum levels of adiponectin are a high risk factor for various types of cancer. Although adiponectin inhibits proliferation and metastasis of breast cancer cells, the underlying molecular ...mechanisms remain obscure. In this study, we show that adiponectin-activated AMPK reduces the invasiveness of MDA-MB-231 cells by stimulating dephosphorylation of AKT by increasing protein phosphatase 2A (PP2A) activity. Among the various regulatory B56 subunits, B56gamma was directly phosphorylated by AMPK at Ser(298) and Ser(336), leading to an increase of PP2A activity through dephosphorylation of PP2Ac at Tyr(307). We also show that both the blood levels of adiponectin and the tissue levels of PP2A activity were decreased in breast cancer patients and that the direct administration of adiponectin into tumor tissues stimulates PP2A activity. Taken together, these findings show that adiponectin, derived from adipocytes, negatively regulates the invasiveness of breast cancer cells by activating the tumor suppressor PP2A.
The alternative analysis of A. Bianchi and M. Savastano is a valuable contribution to the understanding of the complex systems at stake in the complexation chemistry of Zr4+ by considering ...polynuclear species. Placed in the context of nuclear medicine where such aggregates are unlikely and considering recent literature data, this however points out that no clear agreement exists to describe such complex formation.
A series of compounds have been synthesized with a variety of substituents based on a three-carbon chain at the C9-position of 3-hydroxy-
-phenethyl-5-phenylmorphan ...(3-(2-phenethyl-2-azabicyclo3.3.1nonan-5-yl)phenol). Three of these were found to be μ-opioid receptor agonists in the inhibition of forskolin-induced cAMP accumulation assay and they did not recruit β-arrestin at all in the PathHunter assay and in the Tango assay. Compound
(3-((1
,5
,9
)-2-phenethyl-9-propyl-2-azabicyclo3.3.1nonan-5-yl)phenol),
(3-((1
,5
,9
)-9-((
)-3-hydroxyprop-1-en-1-yl)-2-phenethyl-2-azabicyclo3.3.1nonan-5-yl)phenol), and
(3-((1
,5
,9
)-9-(2-hydroxypropyl)-2-phenethyl-2-azabicyclo3.3.1nonan-5-yl)phenol) were partial μ-agonists. Two of them had moderate efficacies (
65%) and one had lower efficacy, and they were
5, 3, and 4 times more potent, respectively, than morphine
. Computer simulations were carried out to provide a molecular basis for the high bias ratios of the C9-substituted 5-phenylmorphans toward G-protein activation.
(-)-
-Phenethyl analogs of optically pure
-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of
SGTPγS binding, ...forskolin-induced cAMP accumulation assay, and MOR-mediated β-arrestin recruitment assays). "Body" and "tail" interactions with opioid receptors (a subset of Portoghese's message-address theory) were used for molecular modeling and simulations, where the "address" can be considered the "body" of the hydromorphone molecule and the "message" delivered by the substituent (tail) on the aromatic ring of the
-phenethyl moiety. One compound, N-p-chloro-phenethynorhydromorphone ((7aR,12bS)-3-(4-chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro3,2-eisoquinolin-7(7aH)-one,
), was found to have nanomolar binding affinity at MOR and DOR. It was a potent partial agonist at MOR and a full potent agonist at DOR with a δ/μ potency ratio of 1.2 in the (
SGTPγS) assay. Bifunctional opioids that interact with MOR and DOR, the latter as agonists or antagonists, have been reported to have fewer side-effects than MOR agonists. The p-chlorophenethyl compound
was evaluated for its effect on respiration in both mice and squirrel monkeys. Compound
did not depress respiration (using normal air) in mice or squirrel monkeys. However, under conditions of hypercapnia (using air mixed with 5% CO
), respiration was depressed in squirrel monkeys.
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