Evaluation of 99mTc-ceftazidime as bacterial infection imaging agent

Although our understanding of microorganisms has advanced significantly and antimicrobial therapy has become increasingly available, infection remains a major cause of patient morbidity and mortality. The use of radiopharmaceuticals for diagnosis of infection is increasing due to their ability to distinguish between septic and aseptic inflammation. A wide range of radiopharmaceuticals have been proposed to visualize infection and inflammation scintigraphically. Ceftazidime a cephalosporin antibiotic used to treat bacterial infections was investigated to label with ^99mTc. Labeling was performed using sodium dithionite as reducing agent at 100 °C for 10 min and radiochemical analysis involved ITLC and HPLC methods. The stability of labeled antibiotic was checked in the presence of human serum at 37 °C up to 24 h. The maximum radiolabeling yield was 95.4 ± 2.0 % corresponding to a specific activity of 178 GBq/mmol. Bacterial binding assay was performed with S. aureus and the in vivo distribution was studied in mice. Images showed minimal accumulation in nontarget tissues, with an average target/nontarget ratio of % 1.4 ± 0.2.     

Evaluation of a new radiolabeled bombesin derivative with 99mTc as potential targeted tumor imaging agent

Gastrin-releasing peptide (GRP) receptors are over-expressed in various human tumor including breast and prostate which can be targeted with bombesin for diagnosis and targeted therapy. High abdominal accumulation and the poor in vivo stability of radiolabeled bombesin analogues may represent a limitation for diagnostic imaging and targeted therapy. In this study a new bombesin derivative was labeled with ^99mTc via HYNIC and tricine as a coligand and investigated further. The peptide HYNIC conjugate was synthesized on a solid phase using 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 human serum at 37 °C up to 24 h. Internalization was studied with the human GRP receptor cell line PC-3. The Biodistribution was studied in mice. Labeling yield of >98 % was obtained to correspond a specific activity of ~80.9 GBq/μmol. Radioconjugate internalization into PC-3 cells was high and specific (15.6 ± 1.9 % at 4 h). A high and specific uptake in GRP-receptor-positive organs such as mouse tumor and pancreas (2.11 ± 0.18 and 1.78 ± 0.09 % ID/g after 1 h respectively) was also determined.     

Radio labeling,quality control and biodistribution of <Superscript>99m</Superscript>Tc-cefotaxime as an infection imaging agent

Cefotaxime, a cephalosporin antibiotic, used to treat bacterial infections was investigated to label with ^99mTc. Labeling was performed using sodium dithionite as a reducing agent at 100 °C for 10 min and radiochemical analysis involved ITLC and HPLC methods. The stability of labeled antibiotic was checked in the presence of human serum at 37 °C up to 24 h. The maximum radiolabeling yield was 92 ± 2%. Bacterial binding assay was performed with S. aureus and the in vivo distribution was studied in mice. Images showed minimal accumulation in non-target tissues, with an average target/non-target ratio of 2.89 ± 0.58.     

Synthesis and preliminary evaluation of 99mTc-spermine as a tumor imaging agent

Polyamines are essential for the growth and survival of all cells with biosynthesis and transportation of polyamines being very active in tumors. With the aim of developing a new tumor imaging agent, the endogenous polyamine, spermine was labeled with ^99mTc, and its characters were also evaluated via in vitro and in vivo studies. ^99mTc-labeled spermine probe (^99mTc-spermine) was synthesized by the direct pretinning procedure and the labeling procedure was optimized with regard to the pH, reaction time, amounts of spermine and SnCl₂. The stability of the ^99mTc-spermine and its capacity to accumulate into 4T1 tumor cells were also evaluated. Biodistribution of ^99mTc-spermine was studied in 4T1 tumor-bearing mice. In the optimal conditions, the whole radiosynthesis was accomplished within 10 min with a decay-corrected yield of 96.5 ± 1.3 % and radiochemical purity of >95 %.^99mTc-spermine was stable at both 37 and 4 °C for at least 6 h. In vitro tests revealed that the ability of ^99mTc-spermine to penetrate in 4T1 tumour cells and an excess of spermine blocked the accumulation of the compound in the models. Biodistribution studies showed a high tumor uptake peaked at 30 min post-injection with 1.82 ± 0.19 % ID%/g. The tumor to muscle uptake ratios of the probe were 3.60 ± 0.51, 4.48 ± 0.29, 4.82 ± 0.18, 5.64 ± 0.10, respectively at 30 min, 1, 2 and 4 h postinjection. Block studies indicated that ^99mTc-spermine had specific binding of tumor via polyamine transport systems. ^99mTc-spermine is a promising radiopharmaceutical in tumor imaging. Further studies are required to determine the usability of ^99mTc–spermine for diagnosis purposes.     

Synthesis,characterization and biodistribution of 99mTc-Bioquin-HMPAO (99mTc-BH) as a novel brain imaging agent

Recently, the development of novel brain imaging agents has aroused much interest thanks to limited number of brain cancer or diseases diagnosis agents. It is aimed to synthesize a novel brain imaging agent including a promise for further studies on AD diagnosis potential and investigate its bioaffinity with biodistribution studies on healthy Balb/c mice. A novel radiolabeled agent was synthesized and characterized. Quality control of ^99mTc-BH was performed utilizing solvent extraction and chromatographic (Radio TLC and Radio HPLC) methods. Bioaffinity of the ^99mTc-BH was investigated on male Balb/c mice at various time points (5, 30, 60, 120 min post-injection). Paper electrophoresis showed that ^99mTc-BH has a neutral structure. Radiochemical purity of ^99mTc-BH was over 95 % with appropriate stability for imaging period. Selected brain regions have uptakes over 4 % ID/g following intravenous injection. Hippocampus has uptake approximately 10 % ID/g. ^99mTc-BH has shown brain uptake, so it may prove to be valuable for brain imaging as a novel technetium-labeled agent. Further investigations with AD animal model are our on going effort to show that this agent has AD diagnosis potential.     

Novel 99mTc labeled σ receptor ligand as a potential tumor imaging agent

A novel 99mTc labeled complex, [N-[2-((2-oxo-2-(4-(3-phenylpropyl)piperazin-1-yl)ethyl) (2-mercaptoethyl)amino)acetyl]-2-aminoethanethiolato]Technetium(V) oxide (PPPE-MAMA′-99mTcO) ([99mTc]-2) has been designed and prepared based on the integrated approach. The corresponding rhenium complex (PPPE-MAMA′-ReO)(Re-2) has been prepared and characterized. In vitro competition binding assays show moderate affinity of Re-2 towards σ1 and σ2 receptors with Ki values of 8.67 ± 0.07 and 5.71 ± 1.88 μmol, respectively. Planar images obtained at 0.5 h, 4 h, 20 h after I.v. Injection indicate the accumulation of [99mTc]-2 in MCF-7 human breast tumor bearing mice at 20 h. Furthermore, the accumulation of [99mTc]-2 has been inhibited at 20 h after co-injection of [99mTc]-2 plus haloperidol (1 mg/kg). Biodistribution studies of [99mTc]-2 display an in vivo tumor uptake of 0.14% ± 0.01% ID/g at 24 h post I.v. Injection with a tumor/muscle ratio of 6.02 ± 0.87. The above results suggest that [99mTc]-2, derived from a previously published lead compound, retains certain tumor uptake and affinity for σ receptors. [99mTc]-2 may be used as a basis for further structural modifications to develop tumor imaging agents with high affinity for σ receptors.     

Synthesis and biodistribution of the 99m TcN-DMSA complex as a potential bone imaging agent

In this study, the preparation of the 99m TcN complex of DMSA (dimercaptosuccinicacid) was carried out as a freeze-dried formulation, through a simple procedureinvolving the initial of 99m TcO 4 – with succinic dihydrazide in thepresence of stannous chloride as reducing agent, followed by the additionof the ligand DMSA to afford the final product. The radiochemical purity ofthe 99m TcN-DMSA complex was over 90% determined by thin layer chromatography.It was stable over 8 hours at room temperature. Its partition coefficientindicated that it was a good hydrophilic complex. Biodistribution in miceshowed that the 99m TcN-DMSA complex was accumulated in bone with high uptakeand good retention, suggesting it would be potentially useful as a bone imagingagent containing the [ 99m TcN] 2+ core. The biodistribution comparison inmice of the 99m TcN-DMSA complex and the 99m Tc-DMSA complex indicate thatthe presence of the 99m Tc nitrido group significantly alters the biologicalproperties of the 99m Tc complex.     

Evaluation of 99mTc-HIDA complex as a cholescintigraphic agent (author's transl)

In the reaction labeling N-(2,6-dimethylphenylcarbamoylmethyl) iminodiacetic acid (HIDA) with 99mTc, several complexes with different chemical characteristics were observed to occur with slight changes in the labeling conditions. Among these complexes, a complex detected in the bile of rats was limited to one complex, named as complex II. The preparation method of 99mTc-HIDA complex II and the exchange reaction between this complex and penicillamine indicate that 99mTc is coordinated with HIDA as low-hydrolyzed 99mTc in this complex. This complex is excreted rapidly through the bile and within 1 hr, about 65% of the total activity injected is recovered from bile in rats. The organ distribution of this complex was studied in mice by radioassay and in rabbits by scintillation camera and, in both cases, the radioactivity was accumulated in the gallbladder. These results suggest that the 99mTc chemical state, low-hydrolyzed state, relates to the bile excretion behavior of this complex, a potentially useful cholescintigraphic agent.     

Biodistribution of the bone imaging agents99mTc-DHPE and99mTc-MDP in rats

The self life of the freeze-dried formulation kits utilized for the preparation of the new bone imaging radiopharmaceutical^99mTc-1,2-dihydroxy-1,2-bis/dihydroxyphosphinyl/ethane /^99mTc-DHPE/ has been investigated as well as the toxicity of the DHPE. In a biodistribution investigation of^99mTc-DHPE in rats, in comparison to^99mTc-methylenediphosphanate /^99mTc-MDP/,^99mTc-DHPE exhibited a certain extent higher skeleton uptake, a higher blood clearance rate, a very low concentration in other organs, a satisfactory biological stability and excretion primarily through the kidneys. These properties demonstrate that^99mTc-DHPE is a new promising skeleton imaging radio-pharmaceutical.     

Synthesis and biodistribution of 99mTcN(PDTC)2as a potential brain imaging agent

The preparation of the bis(N-propyl dithiocarbamato) nitrido technetium-99m complex ^99mTcN(PDTC)₂ (PDTC: N-propyl dithiocarbamato) was carried out as a freeze-dried formulation, through a simple procedure involving the initial of ^99mTcO_4- with succinic dihydrazide in the presence of stannous chloride as reducing agent and propylenediamine tetraacetic acid (PDTA) as complexant, followed by the addition of the ligand sodium salt of N-propyl dithiocarbamate to afford the final product. The radiochemical purity of the complex was over 90%, as measured by thin layer chromatography. No decomposition of the complex at room temperature was observed over a period of 12 hours. Its partition coefficient indicated that it was a good lipophilic complex. Biodistribution in mice showed that the complex accumulated in the brain with high uptake. The brain uptake (ID%/g) was 5.07 and the brain/blood ratio 1.34 at 5-minute post-injection. This suggested a potential usefulness of the complex as a brain perfusion imaging agent. This revised version was published online in July 2006 with corrections to the Cover Date.     

Synthesis and biological evaluation of novel technetium-99m-labeled HYNIC-d-glucose as a potential tumor imaging agent

A conjugate of 6-hydrazinopyridine-3-carboxylic acid (HYNIC) with the d-Glucosamine Hydrochloride (DG) was synthesized though a multiple-step reaction. HYNIC-DG could be labeled successfully and efficiently with ^99mTc using N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine (tricine) and ethylenediamine-N,N′-diacetic acid (EDDA) or tricine and triphenylphosphine-3,3′,3″-trisulfonic acid trisodium salt (TPPTS) as co-ligands to form two ^99mTc-HYNIC-DG complexes ^99mTc-(t/E)HYNIC-DG and ^99mTc-(t/T)HYNIC-DG in high yields (>95 %). The partition coefficient and electrophoresis results indicated they were very hydrophilic and electronegative. The biodistribution studies of two ^99mTc-HYNIC-DG complexes in Kunming mice bearing S 180 tumor showed that ^99mTc-(t/T)HYNIC-DG has more favorable characteristics than ^99mTc-(t/E)HYNIC-DG. High tumor uptake, low or negligible accumulation in non-target organs, and good retention, suggesting ^99mTc-(t/T)HYNIC-DG would be a novel potential tumor imaging agent.     

Synthesis, biodistribution and evaluation of 99mTc-sitafloxacin kit: a novel infection imaging agent

Radiosynthesis of ^99mTc-sitafloxacin (^99mTc-STF) complex and its efficacy as a potential infection imaging agent was evaluated. Effect of sitafloxacin (STF) concentration, sodium pertechnetate (Na^99mTcO₄), stannous chloride dihydrate (SnCl₂·2H₂O), and pH on the % radiochemical purity yield (RCP) of ^99mTc-STF complex was studied. A stable ^99mTc-STF complex up to 120 min with maximum %RCP yield was observed by mixing 2 mg of STF with 3 mCi of Na^99mTcO₄ and 150 μL of SnCl₂·2H₂O (1 μg/μL in 0.01 N HCl) at a pH 5.5. Artificially infected rats with Staphylococcus aureus were used for studying the biodistribution behavior of the ^99mTc-STF complex. After 30 min of the intravenous (I.V.) administration of the ^99mTc-STF complex, 7.50 ± 0.10% was absorbed in the infected thigh of the rats and the uptake gradually increased to 18.50 ± 0.20% within 90 min. Rabbits with artificially induced infection were used for evaluating the scintigraphic accuracy. Higher uptake in the infected thigh was observed after 2 h of I.V. administration of the ^99mTc-STF complex. Target to non-target organ ratio of the % absorbed dose incase of infected/normal muscle was 6.82 ± 0.40, 17.11 ± 0.60, and 23.13 ± 1.00% at 30, 60 and 90 min of administration. Stable and higher %RCP, higher uptake in the infected thigh, and spectral studies, recommend the ^99mTc-STF for routine infection imaging.     

Evaluation and comparison of 99mTc-labeled d-glucosamine derivatives with different 99mTc cores as potential tumor imaging agents

Isocyanide is a strong coordination ligand that can coordinate with [^99mTc(I)(CO)₃]⁺ core and [^99mTc(I)]⁺ core to produce stable ^99mTc complexes, therefore developing a ^99mTc-labeled isocyanide complex for single-photon emission computed tomography (SPECT) imaging is considered to be of great interest. In order to develop potential tumor imaging agents with satisfied tumor uptake and suitable pharmacokinetic properties in vivo, a novel d -glucosamine isocyanide derivative, 4-isocyano-N-(2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)butanamide (CN3DG), was synthesized and radiolabeled with [^99mTc(I)]⁺ and [^99mTc(CO)₃]⁺ cores to obtain [^99mTc(CN3DG)₆]⁺ and [^99mTc(CO)₃(CN3DG)₃]⁺ in high radiolabeling yields (>95%). Both of the complexes showed good hydrophilicity and great stability in vitro. Cell uptake studies performed in S180 cells demonstrated they were transported into cells by glucose transporters. Biodistribution studies of the two complexes in mice bearing S180 tumor showed they had high tumor uptakes and rapid clearance from muscle and blood so that the tumor/blood and tumor/muscle ratios were high. By comparison, [^99mTc(CN3DG)₆]⁺ was superior to [^99mTc(CO)₃(CN3DG)₃]⁺ in regard to tumor uptake, tumor/blood and tumor/liver ratios. S180 tumors could be seen clearly from the SPECT/CT images with [^99mTc(CN3DG)₆]⁺. Considering its favorable properties, [^99mTc(CN3DG)₆]⁺ would be a promising tumor imaging agent and needs to be further studied.     

Synthesis and biodistribution of 99mTcN(CHIPDTC)2 as a potential myocardial perfusion imaging agent

The bis(N-cyclohexyl, N-isopropyl dithiocarbamato) nitrido technetium-99m complex [^99mTcN(CHIPDTC)₂] (CHIPDTC: N-cyclohexyl, N-isopropyl dithiocarbamato) has been synthesized through a ligand-exchange reaction. The two-step procedure involved the initial reaction of ^99mTcO₄ ^- with succinic dihydrazide (SDH) in the presence of stannous chloride as reducing agent and propylenediamine tetraacetic acid (PDTA) as complexant, followed by the addition of the sodium salt of N-cyclohexyl, N-isopropyl dithiocarbamate. The radiochemical purity (RCP) of the complex was 96±2% as measured by thin layer chromatography (TLC). No decomposition of the complex at room temperature (r. t.) was observed within a period of 6 hours. Its partition coefficient indicated that it was a lipophilic complex. The electrophoresis results showed that the complex was neutral. Biodistribution in mice indicated that the complex accumulated in the heart with high uptake and good retention. The heart/blood, heart/lung ratio was 6.28 and 1.35, respectively, at 60-minute post-injection, suggesting that it would be a potential myocardial perfusion imaging agent.     

A tumor mRNA-mediated bi-photosensitizer molecular beacon as an efficient imaging and photosensitizing agent

A bi-photosensitizer molecular beacon (bi-PS MB) is assembled by coupling two PS molecules, respectively, onto the opposite ends of a single MB. The MB can be triggered by a tumor marker-survivin mRNA. Fluorescence and cytotoxic (1)O(2) generation occur effectively in breast cancer cells, but not in normal cells. Compared with a single-PS MB, a bi-PS MB exhibits much-enhanced properties in the signal-to-background ratio and (1)O(2) generation simultaneously.     

Synthesis and biodistribution of a novel 99mTc nitrido radiopharmaceutical with proline dithiocarbamate as a potential tumor imaging agent

In the present study, proline dithiocarbamate (PRODTC) ligand was radiolabeled with the [^99mTc≡N]²⁺ core successfully to obtain the ^99mTcN-PRODTC complex with high radiochemical purity. No decomposition of the complex at room temperature was observed over a period of 6 h. Its partition coefficient indicated that it was a hydrophilic complex. The electrophoresis results showed that the complex was negative. The biodistribution of ^99mTcN-PRODTC in mice bearing S 180 tumor showed that the complex accumulated in the tumor with a certain uptake. The tumor/blood and tumor/muscle ratios reached 2.19 and 4.54 at 2 h post-injection, suggesting it would be a promising candidate for tumor imaging.     

Use of sodium diisobutylaluminum dihydride as a reducing agent

Summary It has been found that sodium diisobutylaluminum dihydride can be applied for the reduction of different functional groups of organic compounds. Both hydrogen equivalents of the complex are utilized.     

99m-Technetium carbohydrate conjugates as potential agents in molecular imaging

This feature article covers recent reports of work towards the development of (99m)Tc-carbohydrate based agents for use in SPECT imaging, particularly of cancerous tissue. An outline of some of the key biological functions and coordination chemistry of carbohydrates is given, along with an introduction to bioconjugation and molecular imaging. Technetium coordination chemistry and the subset of this involving bioconjugates are discussed before moving into the focus of the article: glycoconjugates of (99m)Tc(v) and the more recently developed [(99m)Tc(I)(CO)(3)](+). Significant work in the last decade has featured the very attractive [(99m)Tc(CO)(3)](+) core, and the ligand sets designed for this core are discussed in detail.