Preparation, Biological Evaluation, and First-in-Human Single-Photon Emission Computed Tomography (SPECT) Study of 99mTc-Labeled Prostate-Specific Membrane Antigen (PSMA)-Targeted Radiotracers Containing Triazole with Reduced Kidneys Accumulation.

Prostate-specific membrane antigen (PSMA), a well-established biological marker for prostate cancer (PCa) imaging and therapy, is overexpressed on the surface of prostate cancer lesions. In this study, a triazole ring was introduced into the linker by click chemistry to generate a HYNIC-derived ligand (T), which exhibited good PSMA affinity (Ki = 2.23 nM). Eight stable 99mTc-labeled complexes, [99mTc]Tc-T-Mn (n = 1-8), with hydrophilic properties were synthesized by incorporating different coligands at high radiochemical yields and purities without purification. The radioligands were concentrated in the kidneys of healthy Kunming male mice and were significantly blocked by the PSMA inhibitor ZJ-43. The uptake of the optimized complex [99mTc]Tc-T-M2 was correlated with PSMA, and it had good PSMA affinity (Kd = 5.42 nM). [99mTc]Tc-T-M2 accumulated on LNCaP (PSMA++) tumors and was significantly blocked by ZJ-43 at 2 h p.i., indicating high PSMA specificity. Relatively suitable kidney uptake was beneficial for reducing kidneys exposure in patients. SPECT/CT imaging of [99mTc]Tc-T-M2 in LNCaP (PSMA++) or 22Rv1 (PSMA+) tumor-bearing mice revealed high tumor uptake, low background uptake (especially low kidney uptake (49.06 ± 9.20 %ID/g) at 2 h p.i.), and obvious inhibition by ZJ-43, whereas PC-3 (PSMA-) tumors were undetectable. A freeze-dried [99mTc]Tc-T-M2 kit was successfully developed (T-M2 kit). Preliminary clinical trials showed that [99mTc]Tc-T-M2 clearly identified small prostate cancer lesions and has potential for clinical application.

Enantioselective Synthesis of Chiral Cyclic Hydrazines by Ni-Catalyzed Asymmetric Hydrogenation.

An efficient Ni-(S,S)-Ph-BPE complex that catalyzed asymmetric hydrogenation of cyclic N-acyl hydrazones has been developed to produce various chiral cyclic hydrazines in high yields with excellent enantioselectivities of up to >99% enantiomeric excess. Moreover, the hydrogenation can not only proceed smoothly on a gram scale under lower catalyst loading (S/C = 3000) without any decrease of enantioselectivity but can also be applied to the asymmetric synthesis of a RIP-1 kinase inhibitor.

Enantioselective Synthesis of Chiral Phosphonates via Rh/f-spiroPhos Catalyzed Asymmetric Hydrogenation of ß,ß-Disubstituted Unsaturated Phosphonates.

The first asymmetric hydrogenation of ß,ß-diaryl unsaturated phosphonates has been realized for synthesis of ß,ß-diaryl chiral phosphonates with excellent enantioselectivities (up to 99.9% ee) catalyzed by the Rh-(R,R)-f-spiroPhos complex. Furthermore, this catalyst also exhibits comparably excellent performance for ß-aryl-ß-alkyl unsaturated phosphonates providing the corresponding chiral phosphonates with up to 99.9% ee values. This methodology provides a straightforward access to asymmetric synthesis of chiral phosphonates.

Enantioselective Synthesis of Chiral Substituted 2,4-Diketoimidazolidines and 2,5-Diketopiperazines via Asymmetric Hydrogenation.

An enantioselective hydrogenation of 5-alkylidene-2,4-diketoimidazolidines (hydantoins) and 3-alkylidene-2,5-ketopiperazines catalyzed by the Rh/f-spiroPhos complex under mild conditions has been developed, which provides an efficient approach to the highly enantioselective synthesis of chiral hydantoins and 2,5-ketopiperazine derivatives with high enantioselectivities up to 99.9% ee.

Discrimination of enantiomers of amides with two stereogenic centers enabled by chiral bisthiourea derivatives using 1H NMR spectroscopy.

Enantiomers of a few new amides containing two stereogenic centers have been derived from d- and l-α-amino acids as guests for chiral recognition by 1H NMR spectroscopy. A variety of chiral amides with two or more stereogenic centers often exist in the products of catalytic asymmetric synthesis, natural products or their total synthetic products, and chiral drugs. It would be a challenging and meaningful work to explore their chiral recognition. For this purpose, a class of novel chiral bisthiourea derivatives 1-9 has been synthesized from (1S,2S)-(+)-1,2-diaminocyclohexane, d-α-amino acids, and isothiocyanates as chiral solvating agents (CSAs). CSAs 1-9 proved to afford better chiral discriminating results towards most amides with two stereogenic centers, which have been rarely studied as chiral substrates by 1H NMR spectroscopy. In particular, CSAs 7, 8 and 9, featuring 3,5-bis(trifluoromethyl)benzene residues, exhibit outstanding chiral discriminating capabilities towards all amides, providing well-separated 1H NMR signals and sufficiently large nonequivalent chemical shifts. To test their practical application in the determination of enantiomeric excess, 1H NMR spectra of chiral amides (G16) with different optical purities were measured in the presence of CSAs 7 and 8, respectively. Their ee values (up to 90%) were accurately calculated by the integration of the NH proton of the CONHPh group of G16. To better understand the chiral discriminating behavior, Job plots of (±)-G16 with CSA 7 and (±)-G17 with CSA 8 and the association constants (Ka) of (S,R)-G16 and (R,S)-G16 with CSA 7 were evaluated, respectively. In order to further reveal any underlying intermolecular hydrogen bonding interactions, theoretical calculations of the enantiomers of (S,R)-G16 and (R,S)-G16 with CSA 7 were performed by means of the hybrid density functional theory (B3LYP) with the standard basis sets of 3-21G of the Gaussian 03 program, respectively.

Synthesis of 2-Oxazolines from Ring Opening Isomerization of 3-Amido-2-Phenyl Azetidines.

Chiral 2-oxazolines are valuable building blocks and famous ligands for asymmetric catalysis. The most common synthesis involves the reaction of an amino alcohol with a carboxylic acid. In this paper, an efficient synthesis of 2-oxazolines has been achieved via the stereospecific isomerization of 3-amido-2-phenyl azetidines. The reactions were studied in the presence of both Brønsted and Lewis acids, and Cu(OTf)2 was found to be the most effective.

Highly Efficient Enantioselective Synthesis of Chiral Sulfones by Rh-Catalyzed Asymmetric Hydrogenation.

A highly efficient and enantioselective Rh-( R, R)-f-spiroPhos complex catalyzed hydrogenation of a series of unsaturated sulfones has been developed. With Rh-( R, R)-f-spiroPhos catalyst under mild conditions, not only the asymmetric hydrogenation of both the 3,3-diaryl and exocyclic α,ß-unsaturated sulfones was first realized with up to 99.9% ee but also 3-alkyl-3-aryl and benzo[ b]thiophene-1,1-dioxides were successfully hydrogenated to the corresponding chiral sulfones with excellent enantioselectivities (up to 99.4% ee) regardless of the steric hindrance, electronic property, and geometry of the substrates. Moreover, this reaction offers a route to ( S)-(+)- ar-turmerone as a spice flavor, which is an important synthetic intermediate of pharmaceuticals.

Degradation of phenol in wastewater by cathodic microarc plasma electrolysis.

In this paper, the cathodic microarc plasma electrolysis (CMPE) was tentatively performed to degrade the phenol in aqueous solution by vapor-gaseous envelope discharge around the Ti cathode. Degradation efficiency of phenol was measured and the intermediate products were evaluated. The suspended particles in solution were analyzed and the decomposition mechanism of phenol in the process of cathodic microarc plasma degradation was discussed. The instantaneous current efficiency reached a peak value firstly and then decreased with the discharge time. In the cathodic plasma region, the Cl substituted the hydrogen on benzene ring in the initial time, which was replaced by a hydroxyl immediately, then the polyhydroxy phenol was easily decomposed. In addition, optical emission spectroscopy was carried out to characterize the plasma features during the CMPE process. The temperature of electron around the microarc discharge envelope reached about 4000 K; thus the phenol was partly carbonized to become graphite particles. CMPE is a promising approach to degrade quickly the phenol in wastewater.

A novel high sensitivity sensor for remote field eddy current non-destructive testing based on orthogonal magnetic field.

Remote field eddy current is an effective non-destructive testing method for ferromagnetic tubular structures. In view of conventional sensors' disadvantages such as low signal-to-noise ratio and poor sensitivity to axial cracks, a novel high sensitivity sensor based on orthogonal magnetic field excitation is proposed. Firstly, through a three-dimensional finite element simulation, the remote field effect under orthogonal magnetic field excitation is determined, and an appropriate configuration which can generate an orthogonal magnetic field for a tubular structure is developed. Secondly, optimized selection of key parameters such as frequency, exciting currents and shielding modes is analyzed in detail, and different types of pick-up coils, including a new self-differential mode pick-up coil, are designed and analyzed. Lastly, the proposed sensor is verified experimentally by various types of defects manufactured on a section of a ferromagnetic tube. Experimental results show that the proposed novel sensor can largely improve the sensitivity of defect detection, especially for axial crack whose depth is less than 40% wall thickness, which are very difficult to detect and identify by conventional sensors. Another noteworthy advantage of the proposed sensor is that it has almost equal sensitivity to various types of defects, when a self-differential mode pick-up coil is adopted.

Heteroaromatic and aniline derivatives of piperidines as potent ligands for vesicular acetylcholine transporter.

To identify suitable lipophilic compounds having high potency and selectivity for vesicular acetylcholine transporter (VAChT), a heteroaromatic ring or a phenyl group was introduced into the carbonyl-containing scaffold for VAChT ligands. Twenty new compounds with ALogD values between 0.53 and 3.2 were synthesized, and their in vitro binding affinities were assayed. Six of them (19a, 19e, 19g, 19k, and 24a-b) displayed high affinity for VAChT (Ki = 0.93-18 nM for racemates) and moderate to high selectivity for VAChT over σ1 and σ2 receptors (Ki = 44-4400-fold). These compounds have a methyl or a fluoro substitution that provides the position for incorporating PET radioisotopes C-11 or F-18. Compound (-)-[(11)C]24b (Ki = 0.78 nM for VAChT, 1200-fold over σ receptors) was successfully synthesized and evaluated in vivo in rats and nonhuman primates. The data revealed that (-)-[(11)C]24b has highest binding in striatum and has favorable pharmacokinetics in the brain.

Synthesis and in vitro evaluation of new analogues as inhibitors for phosphodiesterase 10A.

A series of analogues were synthesized by optimizing the structure of papaverine. The in vitro PDE10A binding affinity (IC(50)) values for these new analogues were measured; for compounds that have IC(50) value less than 60 nM for PDE10A, the binding affinities (IC(50) value) for PDE3A and PDE3B were tested. Of these analogues, compounds 6a, 6b, 6n, 8b, 8c and 11 displayed relatively higher PDE10A potency with IC(50) value in the range of 28-60 nM. The most potent compound 1-(4-(2-(2-fluoroethoxy)ethoxy)-3-methoxybenzyl)-6,7-dimethoxyisoquinoline (8c) has the IC(50) value of 28 ± 1.2 nM for PDE10A, 2200 ± 437 nM for PDE3A and 2520 ± 210 nM for PDE3B. Compared to papaverine, compound 8c displayed similar PDE10A potency but improved selectivity to PDE10A versus PDE3A and PDE3B. To identify high potent PDE10A inhibitor, further optimization of the structures of these analogues is necessary.

Synthesis and characterization of selective dopamine D2 receptor ligands using aripiprazole as the lead compound.

A series of compounds structurally related to aripiprazole (1), an atypical antipsychotic and antidepressant used clinically for the treatment of schizophrenia, bipolar disorder, and depression, have been prepared and evaluated for affinity at D(2-like) dopamine receptors. These compounds also share structural elements with the classical D(2-like) dopamine receptor antagonists, haloperidol, N-methylspiperone, domperidone and benperidol. Two new compounds, 7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate (6) and 7-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate (7) were found to (a) bind to the D2 receptor subtype with high affinity (K(i) values < 0.3 nM), (b) exhibit >50-fold D2 versus D3 receptor binding selectivity and (c) be partial agonists at both the D2 and D3 receptor subtype.

Magnesiation of pyridine N-oxides via iodine or bromine-magnesium exchange: a useful tool for functionalizing pyridine N-oxides.

Iodo- or 2-bromopyridine N-oxides were readily magnesiated with i-PrMgCl x LiCl via the iodine or bromine-magnesium exchange. The bromine adjacent to pyridine N-oxide (at the 2- or 6-position) can be regioselectively magnesiated in the presence of other position substituted halogens. This method was tested in various substituted pyridine N-oxide systems, and has been successfully applied to the total synthesis of caerulomycins E and A.

A facile two-step synthesis of 2-arylbenzofurans based on the selective cross McMurry couplings.

A novel two-step synthesis of 2-arylbenzofurans has been developed. It involves a selective cross McMurry coupling of a salicylaldehyde or substituted salicylaldehyde with an aromatic aldehyde and a sequential oxidative cyclization of the resulting ortho-vinylphenols. Utilizing this synthetic protocol, a variety of 2-arylbenzofurans including cicerfuran have been efficiently synthesized.

Synthesis of new chiral cis-3-hydroxyazetidines and their application in diethylzinc addition to aldehydes.

A new series of chiral cis-3-hydroxyazetidines have been prepared from (R)-1-phenylethylamine. They have excellent catalytic activities and enantiomeric selectivities in asymmetric addition of diethylzinc to aromatic aldehydes.

Insights into the general and efficient cross McMurry reactions between ketones.

The selective cross McMurry couplings of diaryl or aryl ketones with various substituted ketones were achieved in 53-94% isolated yields. It is believed that the strong affinity of the substituents to the low-valent titanium surface plays an important role in regards to moderating selectivity. Through the introduction of such substituents followed by their removal post McMurry coupling, structurally similar ketones can be effectively cross-coupled.