Synthesis and biodistribution of <Superscript>99m</Superscript>TcN-isopentyl xanthate as a potential myocardial perfusion imaging agent

A novel ^99mTc nitrido xanthate complex ^99mTcN(IPEXT)₂ (IPEXT: isopentyl xanthate) has been synthesized by the reduction of ^99mTcO₄ ⁻ into [^99mTcN]²⁺ with stannous chloride in the presence of succinic dihydrazide and propylenediamine tetraacetic acid, followed by the addition of the corresponding xanthate ligand. The radiochemical purity of the complex was over 90% as measured by thin layer chromatography (TLC). No decomposition of the complex at room temperature was observed over a period of 6 hours. Its partition coefficient indicated that it was a lipophilic complex. The electrophoresis results showed the complex was neutral. Biodistribution in mice showed that the ^99mTcN(IPEXT)₂ complex accumulated in the heart with high uptake. The heart uptake (%IDg) was 8.00% at 5-minute post-injection, but the heart/lung, heart/liver and heart/blood ratios were not high, thereby, restricting the use of the complex as a good myocardial imaging agent.     

Synthesis and biodistribution of a novel <Superscript>99m</Superscript>Tc-DMSA-metronidazole ester as a potential tumor hypoxia imaging agent

The dimercaptosuccinic acid metronidazole ester (DMSAMe) was synthesized and radiolabeled with ^99mTc to form the ^99mTc-DMSAMe complex in high yield. The radiochemical purity of the ^99mTc-DMSAMe complex was over 90%, as measured by TLC and by HPLC, without any notable decomposition at room temperature over a period of 6 h. Its partition coefficient indicated that it was a lipophilic complex. The tumor cell experiment and the biodistribution in mice bearing S 180 tumor showed that the ^99mTc-DMSAMe complex had a certain hypoxic selectivity and accumulated in the tumor with high uptake and good retention. The tumor/blood and tumor/muscle ratios increased with time, suggesting it would be a possible tumor hypoxia imaging agent.     

Preparation and biodistribution in mice of <Superscript>99m</Superscript>Tc-DTPA-b-cyanocobalamin

Summary Cyanocobalamin (CNCbl), a kind of vitamin B12 (cobalamin, Cbl), which has a special binding capability to rapid dividing cells and proliferating tissue, especially tumors, has been modified and labeled by ^99mTc. The optimal labeling condition was determined, and the biodistribution of ^99mTc-DTPA-b-CNCbl both in normal mice and TA₂ mice bearing MA891 mammary tumors were studied. ^99mTc-DTPA-b-CNCbl showed low uptake and rapid clearance in nontarget tissues, and renal excretion. About 40% of uptake at 1 hour remained in the tumor at 12 hours p.i. The satisfying ratio of T/NT was acquired at 6 hours p.i.     

Synthesis and biodistribution of a novel <Superscript>99m</Superscript>Tc complex of HYNIC-conjugated metronidazole as a potential tumor hypoxia imaging agent

A conjugate of 6-hydrazinopyridine-3-carboxylic acid (HYNIC) with the amino analogue of metronidazole (MN) was synthesized through a multiple-step reaction. HYNIC-MN could be labeled easily and efficiently with ^99mTc using N-(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)glycine (tricine) and ethylenediamine -N,N′-diacetic acid (EDDA) as coligands to form the ^99mTc–HYNIC–MN complex in high yield (>95%). Its partition coefficient indicated that it was a good hydrophilic complex. The tumor cell experiment showed that the ^99mTc–HYNIC–MN complex had a certain hypoxic selectivity. The biodistribution studies of ^99mTc–HYNIC–MN in Kunming mice bearing S180 tumor showed a favorable tissue distribution profile with high tumor uptake, and low or negligible accumulation in non-target organs, suggesting ^99mTc–HYNIC–MN would be a novel potential tumor hypoxia imaging agent.     

Determination of radionuclidic impurities in <Superscript>99m</Superscript>Tc eluate from <Superscript>99</Superscript>Mo/<Superscript>99m</Superscript>Tc generator for quality control

Technetium-99m is the principal radioisotope used in medical diagnostics; radionuclidic impurity is the major concern of its quality. This work presents a analytical method for sequential determination of all radionuclidic impurities listed in pharmacopoeia including gamma emitters, alpha emitters, ⁸⁹Sr and ⁹⁰Sr. Radioactive decay for removal of ^99mTc, ion exchange and extraction chromatography for removal of ⁹⁹Mo and ⁹⁹Tc are effective for separation of interferences. Gamma spectrometry, LSC with alpha/beta discrimination, and Cherenkov counting using LSC are sensitive methods for measurement of the impurity radionuclides. The detection limits of this method are well meet the requirement of the quality control according to the limitation of the pharmacopoeia.     

Preparation,quality control and stability of <Superscript>99m</Superscript>Tc-cefuroxime axetil

Cefuroxime axetil, a cephalosporin antibiotic used to treat bacterial infections, was investigated to label with ^99mTc. Radiolabeling of cefuroxime axetil was carried out by using stannous chloride method. Effects of pH and stannous chloride amount on the radiolabeling yield were investigated. The radiochemical purity of ^99mTc-cefuroxime axetil was determined by thin layer radio chromatography (TLRC), electrophoresis and high performance liquid chromatography. The maximum radiolabeling yield was 98±1%.     

Preparation,characterization and biodistribution of the <Superscript>99m</Superscript>Tc-salicylidenediamine-N-dione complex

A tetradentate set of N₂O₂ salicylaldehyde-amine-N-dione Schiff base was prepared by condensation with salicylaldehyde, ethylenediamine, 2,4-dione and reduction with NaBH₄. The ligand system was characterized by ¹H-NMR and FT-IR spectroscopy and HPLC. Radiolabeling studies of the ^99mTc-complex were performed using stannous ions as the reducing agent. The purity of the complex was determined by ascending solvent system on paper chromatography and instant thin-layer chromatography (ITLC). The yield of the complex was >90%. Biodistribution of the ^99mTc-complex of the precursor was studied in rabbits. A significant uptake and retention of injected activity was observed in the liver and cleared through the bladder. A faint activity was also observed in kidneys. These results indicate that the proposed system may be suitable for development of a liver/spleen imaging agent for future clinical applications.     

Preparation,quality control and physico-chemical properties of <Superscript>99m</Superscript>Tc-BAT-AV-45

One novel styrylpyridine derivatives(AV-45) coupled with ^99mTc complex was synthesized. ^99mTc-BAT-AV-45 was prepared by a ligand exchange reaction employing sodium glucoheptonate, and effects of the amount of ligand, stannous chloride, sodium glucoheptonate and pH value of reaction mixture on the radiolabeling yield were studied in details. Quality control was performed by thin layer chromatography and high performance liquid chromatography. Besides the stability, partition coefficient and electrophoresis of ^99mTc-BAT-AV-45 were also investigated. The results showed that the average radiolabeling yield was (95 ± 1%) and ^99mTc-BAT-AV-45 with suitable lipophilicity was stable and uncharged at physiological pH.     

Synthesis and biodistribution of a novel <Superscript>99m</Superscript>Tc nitrido dithiocarbamate complex containing ether group as a potential myocardial and brain imaging agent

In the present study, a novel ^99mTc nitrido dithiocarbamate complex containing ether group, the bis(2-ethoxyethyl dithiocarbamato) nitrido ^99mTc complex ^99mTcN(EOEDTC)₂ has been synthesized by the reduction of ^99mTcO₄ ⁻ into [^99mTcN]²⁺ with stannous chloride in the presence of succinic dihydrazide and propylenediamine tetraacetic acid, followed by the addition of the corresponding dithiocarbamate ligand. The radiochemical purity of the complex was over 90% as measured by thin layer chromatography (TLC). In vitro studies showed that the complex possessed good stability. Its partition coefficient indicated that it was lipophilic complex. The electrophoresis results showed the complex was neutral. Biodistribution in mice showed that the complex accumulated in the heart and brain with high initial uptake, suggesting the complex may lead to a further development of the radiopharmaceutical as a heart and brain perfusion tracer.     

Synthesis,labeling and biodistribution of <Superscript>99m</Superscript>Tc-3-amino-2-quinoxalin-carbonitrile 1,4-dioxide in tumor bearing mice

3-Amino-2-quinoxalincarbonitrile 1,4-dioxide (AQCD) is a quinoxaline derivative, which was synthesized by condensation method. AQCD was labeled with ^99mTc with labeling yield above 90% investigated by paper chromatography. ^99mTc-AQCD was prepared using stannous chloride as reducing agent at pH 7 and 10 min reaction time. ^99mTc-AQCD should be freshly prepared, otherwise the yield significantly decreased after 15 min post labeling. Stability study of ^99mTc-AQCD reflected the short time stability of Biodistribution study of ^99 mTc-AQCD in tumor bearing mice reflected that its uptake in tumor sites in both ascites and solid tumor sites. This uptake of ^99mTc-AQCD in tumor sites was sufficient to radioimage the inoculated sites.     

Preparation of <Superscript>99m</Superscript>Tc-metronidazole as a model for tumor imaging

Metronidazole (MTNZ) is an antiprotozoa drug, could be labeled with the ^99mTc. MTZL could be used as an ideal vehicle to deliver radioactive decay energy of ^99mTc to the sites of tumor, thus facilitate tumor imaging. The process of labeling was done using tin chloride as reducing agent. The optimum conditions required to label 25 μg MTZL were 100 μg stannous chloride, 30 min reaction time, room temperature at pH 7–9 using 0.5 M phosphate buffer. The radiochemical purity of the labeled compound, at the above conditions, was determined using paper chromatography. The yield was about 93%. About 2.5 × l0⁶ of Ehrlich Ascites Carcinoma (EAC) was injected intrapritoneally (i.p) to produce ascites and intramuscularly (i.m) in the right thigh to produce solid tumor in female mice. Biodistribution studies were carried out by injecting solution of ^99mTc-MTZL in normal and tumor bearing mice. The uptake in ascites was over 5% of the injected dose per gram tissue body weight, at 4 h post injection and above 4% in solid tumor. These data revealed localization of the tracer in the tumor tissues with high percentage sufficient to use ^99 mTc MTZL as promising tool for diagnosis of tumor.     

A novel electrochemical <Superscript>99</Superscript>Mo/<Superscript>99m</Superscript>Tc generator

A novel electrochemical process to avail clinical grade ^99mTc from (n,γ)⁹⁹Mo has been demonstrated. The electrochemical parameters were optimized to maximize the ^99mTc yield with minimal ⁹⁹Mo contamination. ⁹⁹Mo/^99mTc generators containing up to 29.6 GBq (800 mCi) ⁹⁹Mo were developed and their performance were extensively evaluated for 10 days without changing the operating conditions. Very high radioactive concentration of ^99mTcO₄ ⁻ of acceptable quality, commensurate with hospital radiopharmacy requirements could be availed from the system with >90% yield. The compatibility of the product for the formulation of ^99mTc labeled radiopharmaceuticals such as ^99mTc-DMSA and ^99mTc-EC was found to be satisfactory in terms of high labeling yields. The proposed route represents an important step for enhancing the scope of accessing clinical grade ^99mTc from low specific activity (n, γ)⁹⁹Mo.     

Biodistribution and imaging of <Superscript>99m</Superscript>Tc-MAVGG-adenine in tumor bearing mice

To increase the tumor uptake of Val-Gly-Gly (VGG), adenine was introduced into the peptide. N-mercaptoacetyl-VGG-adenine (MAVGG-adenine) and MAVGG were labeled with ^99mTc using a solution of SnCl₂ and tartaric acid as reducing agent. Biodistribution in mice bearing the S180 tumor was measured and γ imaging was performed. Compared with MAVGG, adenine conjugated MAVGG had higher tumor uptake and tumor to normal tissue ratios, which suggested that the tumor uptake property of a peptide may be improved by introducing a nucleotide base. The high contrasted tumor images of ^99mTc-MAVGG-adenine also suggested its potential utility as tumor imaging agent.     

Synthesis and evaluation of a new bombesin analog labeled with <Superscript>99m</Superscript>Tc as a GRP receptor imaging agent

Tumors such as prostate, small cell lung cancer, breast, gastric and colon cancer are known to overexpress receptors to bombesin (BBN). In this study, a new bombesin analogue was labeled with ^99mTc via HYNIC and tricine/EDDA as coligands and investigated further. HYNIC-GABA-Bombesin (7–14) NH₂ was synthesized using a standard Fmoc strategy. Labeling with ^99mTc was performed at 100 °C for 10 min and radiochemical analysis involved ITLC and HPLC methods. The stability of radiopeptide was checked in the presence of humane serum at 37 °C up to 24 h. The receptor bound internalization and externalization rates were studied in GRP receptor expressing PC-3 cells. Biodistribution of radiopeptide was studied in nude mice bearing PC-3 tumor. Labeling yield of >98% was obtained corresponding to a specific activity of ~2.6 MBq/nmol. Peptide conjugate showed good stability in the presence of human serum. The radioligand showed high and specific internalization into PC-3 cells (14.63 ± 0.41% at 4 h). In biodistribution studies, a receptor-specific uptake was observed in GRP-receptor-positive organs so that after 4 h the uptakes in mouse tumor and pancreas were 1.31 ± 0.18 and 1.2 ± 0.13% ID/g, respectively.     

Evaluation of fresh and old eluate of <Superscript>99</Superscript>Mo/<Superscript>99m</Superscript>Tc generators used for labeling of different pharmaceutical kits

Summary Sixty ⁹⁹Mo/^99mTc wet column generators, loaded with two different ⁹⁹Mo activities, were analyzed in order to assess the quality of their eluates. Each elution was used for labeling of different radiopharmaceuticals, in order to evaluate whether “risky” elutions, namely those performed just after generator delivery and at 72 hours or more from the last elution, could be conveniently employed when fresh available radioactivity is not enough for the planned labeling or when shipping problems arise, or delay in delivery of a new generator occurs. Radiochemical quality control of all radiopharmaceuticals labeled with these elutions was performed. The elutions differed mainly in ⁹⁹Tc ground state (^99gTc) and amounts of oxidizing impurities. Radiolabeling procedures, however, were not affected, suggesting that these “risky” elutions might be appropriately used, in “emergency” conditions, for labeling radiopharmaceuticals although their radiochemical purity control is recommended prior to patient administration.     

Synthesis and biodistribution of the <Superscript>99m</Superscript>Tc(CO)<Subscript>3</Subscript>-DEDT complex as a potential new radiopharmaceutical for brain imaging

The ^99mTc(CO)₃(H₂O)-DEDT complex was prepared by a two-step procedure involving the preparation of the precursor fac-[^99mTc(CO)₃(H₂O)₃]⁺, followed by the addition of sodium salt of diethyl dithiocarbamate (DEDT). The radiochemical purity (RCP) of the product was over 90% as measured by thin layer chromatography (TLC). No decomposition of the complex at room temperature was observed over a period of 6 hours. Its partition coefficient indicated that it was a lipophilic complex. The electrophoresis results showed the complex was neutral. Biodistribution in mice demonstrated that the complex can penetrate the intact blood-brain barrier (BBB) and the brain uptake (ID%/g) was 4.22 at 5-minute post-injection, suggesting the complex may lead to a further development of the radiopharma ceutical as a brain perfusion tracer.     

Synthesis and biological evaluation of a novel <Superscript>99m</Superscript>Tc complex of HYNIC-conjugated aminomethylenediphosphonate as a potential bone imaging agent

A conjugate of 6-hydrazinopyridine-3-carboxylic acid (HYNIC) with aminomethylenediphosphonic acid (AMDP) was synthesized through a multiple-step reaction. HYNIC–AMDP could be labeled easily and efficiently with ^99mTc using N-(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)glycine (tricine) as coligand to form the ^99mTc–HYNIC–AMDP complex in high yield (> 95%). Its partition coefficient indicated that it was a good hydrophilic complex. The biodistribution studies of ^99mTc–HYNIC–AMDP in normal ICR mice showed that this complex had high bone uptake and low or negligible accumulation in non-target organs. As compared with ^99mTc–MDP, ^99mTc–HYNIC–AMDP had a higher bone uptake and the ratios of bone/blood and bone/muscle at early time after injection, suggesting that it could be potentially useful for bone imaging at an earlier time after injection according to further investigations of the biological behavior of this complex.     

Synthesis,radiochemical and biological characteristics of <Superscript>99m</Superscript>Tc-8-hydroxy-7-substituted quinoline complex: a novel agent for infection imaging

2,2′-[(8-hydroxyquinolin-7-yl)methylazanediyl]diacetic acid (HQMADA) was synthesized via reaction of 8-hydroxyquinoline with iminodiacetic acid in presence of paraformaldehyde with a yield of 27%. The obtained compound was well characterized via different analytical techniques. Labeling of the synthesized compound with technetium-99m in pertechnetate form (^99mTcO₄ ⁻) in the presence of stannous chloride dihydrate was carried out via chelation reaction. The reaction parameters that affect the labeling yield such as HQMADA concentration, stannous chloride dihydrate concentration, pH of the reaction mixture, and reaction time were studied to optimize the labeling conditions. Maximum radiochemical yield of ^99mTc-HQMADA complex (91.9%) was obtained by using 1.5 mg HQMADA, 50 μg SnCl₂·2H₂O, pH 8 and 30 min reaction time. Biodistribution studies in mice were carried out in experimentally induced infection in the left thigh using E. coli. ^99mTc-HQMADA complex showed higher uptake (T/NT = 5.5 ± 0.3) in the infectious lesion than the commercially available ^99mTc-ciprofloxacin (T/NT = 3.8 ± 0.8). Biodistribution studies for ^99mTc-HQMADA complex in Albino mice bearing septic and aseptic inflammation models showed that ^99mTc-HQMADA complex able to differentiate between septic and aseptic inflammation.     

Water-soluble derivatives of chitosan as a target delivery system of <Superscript>99m</Superscript>Tc to some organs in vivo for nuclear imaging and biodistribution

Carboxymethyl chitosan, (CMC), and N-lauryl-carboxymethyl chitosan (LCMC), have been prepared as water soluble derivatives of chitosan. These biodegradable chitosan derivatives were characterized and investigated for nuclear imaging and body distribution. They were labeled with ^99mTc to use them as targeted delivery to some organs in vivo for nuclear imaging and to follow their biodistribution within the body. The factors controlling the labeling efficiency have been investigated. The percent labeling yield was determined by using ascending paper chromatographic technique. In vivo biodistribution studies of radiolabeled chitosan derivatives were carried out in groups of female Wistar rats, the body distribution profile in rat was recorded by gamma scintigraphy and the biodistribution of ^99mTc-labeled compounds in each organ was calculated as a percentage of the injected dose per gram of tissue (%ID/g). It has been found that the biodistribution of the two compounds and the pattern of their liver uptake were markedly different. The present study demonstrates a high potential approach for liver imaging using ^99mTc-LCMC. An intriguing finding of this study was that the three samples were excreted rapidly via the kidneys because of the water-soluble nature of chitosan derivatives. This suggests that water-soluble chitosan derivatives are good polymeric carriers for radioactive element that overcomes accumulation in the body. Moreover, the easy and inexpensive availability of chitosan could be beneficial for applications in scintigraphic imaging.     

<Superscript>99m</Superscript>Tc-roxifiban: a potential molecular imaging agent for the detection and localization of acute venous thrombosis

^99mTc-roxifiban was obtained in a high radiochemical yield (98.4%) by complexing ~750 MBq ^99mTc with 2.5 mg roxifiban in the presence of 150 µg SnCl₂·2H₂O. Factors affecting the labelling yield were investigated and optimized. The complex was lipophilic and stable in saline and serum for more than 8 h. The complex structure prediction and molecular docking to its target activated GPIIb/IIIa receptor were performed. The tracer in vitro binding to activated platelets was high (27–32%). In vivo evaluation was performed through clearance, biodistribution and imaging studies in rats. All results supported the usefulness of the tracer as thrombus imaging agent.