Study on tumor affinity of technetium-99m-labeled radiopharmaceuticals. (1) 99mTc-pertechnetate, 99mTc-human serum albumin, and 99mTc-trasylol]

This paper describes biologic distributions, sequential images and macroautoradiograms of 99mTcO4 (pertechnetate), 99mTc-Sn-HSA (human serum albumin) and 99mTc-Sn-TSL (trasylol) in tumor-bearing mice as the first report on tumor affinity of 99mTc-labeled radiopharmaceutical. (1) Maximum tumor concentration (% administered dose/g of tissue weight) of 99mTcO4, 99mTc-HSA and 99mTc-TSL in Ehrlich's tumor-bearing mice resulted in 2.03+/-0.57 at 1 hr, 4.02+/-0.19 at 3 hr and 1.97+/-0.31 at 1 hr respectively. (2) However, tumor to blood concentration ratio of 99mTc-HSA was lowest among them. (3) The corrected tumor accumulation (% 100g dose/g of tissue wt.=% dose/% body weight) of 99mTc-TSL to Ehrlich's tumor in mouse was not different from that of Yoshida's sarcoma in rat, on the contrary to our expectation that the tumor concentration of 99mTc-TSL in them might be different due to differency of the tissue fibrinolytic activity between the respective tumors. (4) Sequential images of the implanted tumor in mouse was best positively delineated with 99mTc-HSA. (5) Macroautoradiograms of Ehrlich's tumor with 99mTcO4, 99mTc-HSA and 99mTc-TSL demonstrated the following findings: all of them were not only accumulated markedly into the tumor cells which were shown as basophilic tissue with H?matoxylin-Eosin staining but also accumulated around the tumor tissue and on the interstitial tissue which were stained as eosinophilic tissue with the above same staining.     

Tumor affinity of 99mTc-labeled radiopharmaceuticals, 99mTc-Sn-urokinase and 99mTc-Sn-mannitol

Biolgic distribution of 99mTc-labeled fibrinolytic agent, urokinase, and 99mTc-labeled mannitol, which was obtained as a side-product in the preparation of 99mTc(Sn)-urokinase, have been studied in Ehrlich's tumor-bearing mice to get a promising indicator for the positive delineation of malignant tumor. The preparation of 99mTc-labeled radiopharmaceuticals, 99mTc-UK and 99mTc-Man, was made by the reduction with stannous chloride and labeling efficiency was examined by Sephadex G-25M gel chromatography and by silica gel plate thin layer chromatography. Labeling yield of 99mTc-UK by Sephadex G25M in 0.9% NaCl eluant was 13% and that of 99mTc-Man by TLC in 85% methanol solvent was over 95%. A higher uptake to the implanted solid tumor tissue in mice was found in 99mTc-Man than in 99mTc-UK, of which the excellent tumor accumulation was expected from the positive delineation of malignant tumor with 131I-fibrinogen, 131I-fibrinogen antibody and 125I-plasmin. The poor result in 99mTc-UK, however, may be attributed to the poor fibrinolytic activity of Ehrlich's tumor. In biologic distribution of 99mTc-UK was found high concentration for liver kidney and stomach. In the other hand, a higher tumor tissue uptake, a fast blood disappearance and a low concentration for different organs were found in biologic distribution of 99mTc-Man. Therefore, 99mTc-Man may be assumed as a more preferable 99mTc-labeled tumor localizing radiopharmaceuticals, to which it would be needed as absolute biologic characteristics that 99mTc-labeled compounds possess a high tumor uptake as well as a fast blood disappearance with a low uptake for different organs. However, the possible delineation with 99mTc-labeled fibrinolytic agents, including urokinase and streptokinase, may be promised for malignant tumors in human-subject, which generally have a higher activity in fibrinogenesis than in fibrinolysis.     

Separation of99mTc from neutron-irradiated MoO3 by precipitation as CaMoO4

A method is discussed for separating^99mTc from⁹⁹Mo by dissolution and reprecipitation of CaMoO₄ containing⁹⁹Mo-^99mTc.^99mTc can be obtained successfully with a yield of about 80% and with a radionuclidic purity as high as over 99.7%. On the other hand, by agitating Ca⁹⁹ MoO₄ solid with 0.9% NaCl aqueous solution,^99mTc can directly be obtained with a yield of about 30% without any impurities.     

Synthesis, radiolabeling and biological evaluation of propylene amine oxime complexes containing nitrotriazoles as hypoxia markers

Two propylene amine oxime (PnAO) complexes, 1, containing a 3-nitro-1,2,4-triazole and 2, containing two 3-nitro-1,2,4-triazoles, were synthesized and radiolabeled with (99m)Tc in high labeling yields. Cellular uptakes of (99m)Tc-1 and (99m)Tc-2 were tested using a S180 cells line. Under anoxic conditions, the cellular uptakes of (99m)Tc-1 and (99m)Tc-2 were 33.7 ± 0.2% and 35.0 ± 0.7% at 4 h, whereas the normoxic uptakes of the two complexes were 6.0 ± 1.6% and 4.6 ± 0.9%, respectively. Both (99m)Tc-1 and (99m)Tc-2 displayed significant anoxic/normoxic differentials. The cellular uptakes were highly dependent on oxygen and temperature. Biodistribution studies revealed that both (99m)Tc-1 and (99m)Tc-2 showed a selective localization in tumor and slow clearance from it. At 4 h, the tumor-to-muscle ratios (T/M) were 3.79 for (99m)Tc-1 and 4.58 for (99m)Tc-2. These results suggested that (99m)Tc-labeled PnAO complexes (99m)Tc-1 and (99m)Tc-2 might serve as novel hypoxia markers. By introducing a second nitrotriazole redox center, the hypoxic accumulation of the marker was slightly enhanced.     

<Superscript>99</Superscript>Mo/<Superscript>99m</Superscript>Tc generators based on aluminum molybdate gel matrix prepared by nano method

A procedure for preparation of ⁹⁹Mo/^99mTc radioisotope generator based on low specific activity neutron activated ⁹⁹Mo was developed. Aluminum molybdate(VI)-⁹⁹Mo of high Mo(VI) content (~?364 mg/g Al⁹⁹Mo) was prepared by mixing low specific activity molybdate(VI)-⁹⁹Mo and aluminum mixture solution with isoamyl alcohol. Al⁹⁹Mo gel matrix was precipitated when the pH of the mixture solution was raised to ~?5 by addition of NaOH to the mixture. Radiometric measurements indicate the strong fixation of Molybdate(VI)-⁹⁹Mo species in the form of the sparingly insoluble Al⁹⁹Mo gel matrix. The prepared AlMo gel matrix was physiochemically characterized. Al⁹⁹Mo gel matrix was used as a base material for preparation of ⁹⁹Mo/^99mTc generator. The ^99mTc eluted from ⁹⁹Mo/^99mTc radioisotope generator was found to have relatively high elution yield (84?±?2.3%), radionuclidic (≥?99.99%), radiochemical (98.1?±?0.9%) and chemical purity.     

Pharmaceutical grade sodium [99mTc] pertechnetate from low specific activity 99Mo using an automated 99Mo/99mTc-TCM-autosolex generator

Performance study of a computer controlled automated closed cyclic module for the separation and recovery of ^99mTc from low specific activity (n, γ) ⁹⁹Mo using methyl ethyl ketone (MEK) solvent extraction technique named ⁹⁹Mo/^99mTc-TCM-AUTOSOLEX (Technetium automated solvent extraction) Generator is described. The entire system is automated and controlled by a user-friendly PC based graphical user interface that actually supervises process via an embedded system based electronic controller. The average yield of separation of ^99mTc was above 85 % and ⁹⁹Mo breakthrough in ^99mTc pertechnetate was <0.002 %. The sodium pertechnetate obtained was a clear solution having pH 6–7, Radiochemical (RC). Purity >99 %, MEK content <0.1 % (v/v), Al and Mo content <10 µg/ml. R. C. Purity of ^99mTc-radiopharmaceuticals studied was not less than 96 %. Bio-Quality control studies confirm that sodium pertechnetate obtained was sterile and pyrogen free. Imaging studies in animals and humans with limited radiopharmaceuticals show that the quality of ^99mTc-pertechenate obtained in the present module was good enough to do clinical study.     

Chemical and biological properties of verapamil labeled with technetium-99m: A potential myocardial imaging agents

On the base of property to enter into myocardial cells as a calcium channel blocker, verapamil was labeled with technetium-99m in order to investigate the possibility to obtain new radiopharmaceutical for myocardial imaging. The conditions of labeling verapamil with technetium-99m for different ammounts of stannous(II) ion, mannitol, cystein and pH range 2.5–3.5 were examined. Investigation of radiochemical purity (>95%) and biodistribution of ^99mTc-verapamil in rats showed that it was stable during 2 hours after labeling. Accumulation of ^99mTc-verapamil in heart was 1.2% and in liver 9.4%, 5 minutes after injection. Biodistribution of ^99mTc-verapamil in rats in conditions of stress, pharmacologically caused by dipiridamol, showed that the elimination of ^99mTc-verapamil from the heart was slower related to the control group. In the group of rats previously treated with isoproterenol uptake of ^99mTc-verapamil in heart was lower related to the control group (0.7% versus 1.0%) 5 minutes after injection. Lipophilicity of ^99mTc-verapamil was examined by determination of partition coefficient (log P = 0.62) and protein binding (79%). Imaging studies on dogs provided relatively good myocardial images with partially overlap of activity in the lung and liver.     

New99mTc-diiodine substituted IDA derivative (DIIODIDA) for hepatobiliary imaging

A new diiodine substituted IDA derivative, 2,4-diiodine-6-methyl IDA (DIIODIDA) was synthesized and labeled with^99mTc. It was established that^99mTc-DIIODIDA had high radiochemical purity. Biodistribution and influence of bilirubin on^99mTc-DIIODIDA biokinetics has been studied in rats and compared to the corresponding results for^99mTc-SOLCOIODIDA. Related to^99mTc-SOLCOIODIDA,^99mTc-DIIODIDA has much better biliary exretion (55.18 versus 43.63%). No change of^99mTc-DIIODIDA biokinetics, under influence of bilirubin was noticed. Biliary excretion of^99mTc-SOLCOIODIDA has been reduced for about 60%. The protein binding of^99mTc-DIIODIDA and^99mTc-SOLCOIODIDA were also determined, using in vitro method of precipitation. These results showed that^99mTc-DIIODIDA hepatobiliary imaging agent is superior to the presently used^99mTc-monoiodine IDA derivatives.     

苯甘氨酰胺结晶诱导的动态动力学拆分

以取代水杨醛为消旋催化剂,通过加入手性助剂,实现了苯甘氨酰胺结晶诱导的动态动力学拆分.在优化条件下,单程收率达82％以上,光学纯度达99％ ee.手性助剂可以回收,含消旋催化剂的母液可以循环套用,三次套用的平均收率高达99％,光学纯度＞99％ ee.     

Highly enantioselective bioreduction of ethyl 3-oxohexanoate

Seven wild-type microorganism strains were used to reduce ethyl 3-oxohexanoate to ethyl (R)-3-hydroxyhexanoate. Free cells of Kluyveromyces marxianus and Aspergillus niger led to higher than 99% of conversion with higher than 99% ee. After immobilization in calcium alginate spheres, cells of K. marxianus exhibited high enantioselectivity (>99% ee) and conversion level (99%) within 24 h even if substrate was added at concentration of 10 g/L (62 mM).     

N-heterocyclic carbene (NHC)-catalyzed highly diastereo- and enantioselective oxo-Diels-Alder reactions for synthesis of fused pyrano[2,3-b]indoles

A chiral N-heterocyclic carbene (NHC)-catalyzed Diels-Alder reaction of 2-oxoindolin-3-ylidenes and α-chloroaldehydes was developed for the synthesis of fused pyrano[2,3-b]indoles in good to excellent yields (up to 99%) with high cis-diastereoselectivities (>99:1 dr) and enantioselectivities (up to >99% ee).     

Determination of multi-pesticide residues in cereals, cereal products and animal feed using gel-permeation chromatography

Residues of organophosphorus, organochlorine and synthetic pyrethroid pesticides and insect growth regulators were determined in cereals and cereal products. Samples were extracted with acetone-methanol and the extracts cleaned-up by gel-permeation chromatography. The mean recoveries were: 99%, organophosphorus; 94%, organochlorine; 99%, synthetic pyrethroid; and 99%, insect growth regulators.     

99mTc(CO)3-labeled pamidronate and alendronate for bone imaging

Bone scintigraphy with (99m)Technetium-methylenediphosphonate ((99m)Tc-MDP) or (99m)Technetium-hydroxymethylenediphosphonate ((99m)Tc-HMDP) presents several limitations, namely low specificity, uncertainty in the radiopharmaceutical's molecular structure and long acquisition time after injection. Aiming to find bone-seeking radiotracers based on the core fac-[(99m)Tc(CO)(3)](+) with improved chemical and biological properties, we synthesized new conjugates (pz-PAM and pz-ALN), comprising a pyrazolyl-diamine chelating unit (pz: N,N,N donor atom set) for metal stabilization and a pendant pamidronate (PAM) or alendronate (ALN) moiety for bone targeting. The reaction of the conjugates with fac-[(99m)Tc(CO)(3)](+) yielded (> 95%) the stable complexes fac-[(99m)Tc(CO)(3)(pz-PAM)](-) (2a) and fac-[(99m)Tc(CO)(3)(pz-ALN)](-) (3a), which have been characterized by comparing their HPLC gamma-traces with the UV-vis traces of the Re surrogates 2 and 3, respectively. 2a and 3a bind strongly onto hydroxyapatite. The biodistribution studies in Balb-c mice have shown that 2a and 3a presented an high bone uptake (2a 18.3 ± 0.6% I.D./g, 3a 17.3 ± 6.1% I.D./g, at 1 h post injection), similar to (99m)Tc-MDP (17.1 ± 2.4% I.D./g, at 1 h post injection), with comparable clearance from most tissues and increased total excretion (2a 66% I.D., 3a 67% I.D. and (99m)Tc-MDP 49% I.D., at 1 h post injection). The bone-to-blood (2a 86.2, 3a 74.7) and the bone-to-muscle ratios (2a 77.7, 3a 79.0) are higher than the ones found for (99m)Tc-MDP (70.9, 47.9), at 4 h post injection. Planar whole-body gamma camera images of the rats injected with the (99m)Tc(CO)(3)-labeled pamidronate (2a) and alendronate (3a) confirmed the overall adequate biological profile of the new radiotracers for bone imaging.     

Quality control and statistical analysis of biodistribution of commercial99mTc-IDA derivatives

The results obtained for radiochemical purity of ITLC (SA) and (SG) using different solvent systems and low voltage electrophoresis are presented in the paper. Radiochemical purities obtained for^99mTc-dimethyl IDA (^99mTc-HIDA) and^99mTc-diethyl IDA (^99mTc-EHIDA) are 98.1±0.6% and 98.7±0.5%, respectively. Variable^99mTc hydrolyzate contents, depending on the ionic strength of the eluents and on the time interval between labelling and analysis, have been obtained by Sephadex chromatography. The eluent containing Sn-EHIDA inhibits dissociation of^99mTc-EHIDA due to dilution of the preparation during elution of the column and yielding only a small percent of Sephadex bound fraction, as compared to other investigated eluents. The range of normal^99mTc-IDA biodistribution values in the organs of experimental animals and statistical significance of the difference between these two preparations have also been determined. The results obtained for^99mTc-HIDA and^99mTc-EHIDA in the liver are 33.9±5% and 25.7±4.7%, respectively p<0.01.     

One pot iridium-catalyzed asymmetrical double allylations of sodium sulfide: a fast and economic way to construct chiral C2-symmetric bis(1-substituted-allyl)sulfane

One pot asymmetrical double allylations of sodium sulfide catalyzed by an iridium complex along with a combination of caesium fluoride and water in dichloromethane have been realized and the double allylation products with two C-S bond chiral centers were obtained in 67-99% yields with b/l 81/19-99/1, dr 85/15-99/1, and 96-99% ee.     

Preparation of Optically Enriched Secondary Alkyllithium and Alkylcopper Reagents—Synthesis of (−)‐Lardolure and Siphonarienal

Optically enriched secondary alkyl iodides were converted into secondary alkyllithium and secondary alkylcopper compounds with very high retention of configuration. Quenching with various electrophiles, including chiral epoxides, provided a range of chiral molecules with high enantiomeric purity (>90 % ee). This method has been applied in an iterative fashion in the total synthesis of (?)‐lardolure in 13 steps and 5.4 % overall yield (>99 % ee, dr>99:1) and siphonarienal in 15 steps and 5.6 % overall yield (>99 % ee, dr>99:1) starting from commercially available ethyl (R)‐3‐hydroxybutyrate (>99 % ee).     

Labeling of polyaminomacrocyclic ligands BY99mTcO 4 − reduction and exchange reactions

The cationic^99mTc-complexes of 1,4,8,12-tetraazacyclopentadecane (15-ane-N₄), 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane (Me₄cyclam) and 1,4,7,10,13,16-hexaazacyclooctadecane (hexacyclen) are obtained in yields higher than 80% by^99mTcO ₄ ^– reduction at pH 12. The electrophoretic and chromatographic analyses show that these ligands form structurally similar complexes. Efficient labeling of 15-ane-N₄ (>95%) is obtained by the exchange reaction with^99mTc-citrate,^99mTc-ENDA and^99mTc-HBA at pH 12. The labeling yield of hexacyclene is 70% and 85% following the reaction with^99mTc-ENDA and^99mTc-HBA and^99mTc-citrate, respectively. The labeling of Me₄cyclam is very poor (about 10%) except starting from^99mTc-citrate (55%). The results are compared wint the available data for well characterized [TcO₂L]⁺ complexes.     

Clinical significance of 99mTc-N-pyridoxyl-5-methyltryptophan (99mTc-PMT) in the diagnosis of intrahepatic masses

Hepatobiliary scintigraphy with 99mTc-N-pyridoxyl-5-methyltryptophan (99mTc-PMT) was carried out on 48 patients with intrahepatic masses, 44 with hepatocellular carcinoma and one each of hepatocellular adenoma, focal nodular hyperplasia, cholangiocellular carcinoma, and adenoid cystic carcinoma. Scans were performed twice, early scan (30 min post i.v.) and delayed scan (2.5 h post i.v.), and the delayed scan was used for assessing the accumulation of 99mTc-PMT in the intrahepatic masses. In the hepatocellular carcinoma group, based on individual patients, 17 out of 44 (38.6%) showed accumulation of 99mTc-PMT in various degrees; and based on individual masses, accumulation was noted in 21 out of 55 masses (38.2%). However, only the cases which had not received transarterial infusion of anti-cancer drugs (TAI) and/or blocking agents (TAE) were taken into consideration, 9 out of 18 patients (50%) and 12 out of 25 masses (48.0%) were found capable of picking up 99mTc-PMT. A case of hepatocellular adenoma showed a strong accumulation of 99mTc-PMT in the mass which was depicted as a defect on the 99mTc-colloid scan and did not show a significant accumulation of 67Ga. In a case of focal nodular hyperplasia, there were two space-occupying lesions (SOLs), one of which showed a clear-cut defect on the 99mTc-colloid scan and the other which showed only a distorted uptake pattern. However, both masses were strongly positive with 99mTc-PMT. 99mTc-PMT scintigraphy is useful in connection with 99mTc-colloid scan and sometimes with 67Ga-citrate in the diagnosis of intrahepatic masses originating from hepatocytes.     

Organocatalytic sequential Michael reactions: stereoselective synthesis of multifunctionalized tetrahydroindan derivatives

Multifunctionalized tetrahydroindan derivatives with four stereocenters were constructed via two sequential Michael reactions between cyclic γ,δ-unsaturated-β-ketoester and nitroalkenes initiated with 0.5-2 mol % of cinchona alkaloid based bifunctional organocatalysts and then with 1 equiv of tetramethylguanidine for cyclization. The desired products could be obtained in high yields (up to 99% yield) with excellent enantioselectivities (95-99% ee) as well as diastereoselectivities (up to >99:1 dr) even on a gram scale.     

Stereoselective synthesis of new monoterpene β-amino alcohols

The regio- and stereoselective osmium-catalysed aminohydroxylation of (+)-2-carene (99% ee), and (+)-3-carene (99% ee), (?)-β-pinene (99% ee) and (?)-camphene (75% ee) with chloramine-T is described. The products β-hydroxy-p-toluenesulfonamides were reduced with sodium in liquid ammonia to give the corresponding β-amino alcohols with 48–83% yields. The methylation-reduction of β-hydroxy-p-toluenesulfonamides gave β-methylamino alcohols with 33–55% yields.