Preparation,characterization and biodistribution of a new technetium‐99 m nitrido complex with 2‐methoxyisobutylisonitrile and comparison with 99mTc–MIBI

The preparation of complex ^99mTcN–MIBI was carried out using two alternative procedures that led to the formation of the complex with high radiochemical purity (>90%). The partition coefficient, electrophoresis and cationic resin exchange experiments showed that the ^99mTcN–MIBI is a lipophilic and neutral complex, the structure of this complex is six‐coordinate distorted octahedral, its composition may be [^99mTcNCl₂(MIBI)₃], and the optimized geometry of this complex was calculated by using Gaussian 98 for Window (G98W) program. The biodistribution of ^99mTcN–MIBI shows high myocardial uptake and good target/non‐target ratios in mice at early post‐injection time, for 5 min post‐injection the heart‐to‐blood, heart‐to‐lungs and heart‐to‐liver ratios are 3.18, 1.72 and 1.42, respectively. In respect of the relatively good rations after 5 min and the rapid clearance from non‐target, the complex ^99mTcN–MIBI may be suitable for instant myocardial imaging. In addition, the lyophilized kit enables the convenient preparation of this complex for clinical use. Based on these promising properties, ^99mTcN–MIBI should be a new potential myocardial perfusion‐imaging agent. Copyright © 2002 John Wiley & Sons, Ltd.     

Preparation and biological evaluation of 99mTcN‐labeled pteroyl‐lys derivative as a potential folate receptor imaging agent

In order to develop a novel ^99mTc‐labeled folate receptor (FR) imaging agent, a dithiocarbamate derivative, pteroyl‐lys‐DTC, was synthesized and radiolabeled with ^99mTc through the [^99mTcN]²⁺ intermediate. The radiochemical purity of the corresponding ^99mTc‐complex, ^99mTcN‐pteroyl‐lys‐DTC, was over 95% as measured by reversed‐phase HPLC. The ^99mTcN complex was stable under physiological conditions. ^99mTcN‐pteroyl‐lys‐DTC exhibited specific FR binding in FR‐positive KB cells in vitro. The biodistribution in tumor‐bearing mice showed that the ^99mTcN‐labeled radiotracer had good uptake (3.56 ± 0.09%ID/g at 2 h postinjection) in FR‐positive KB tumors, as well as in the kidneys (30.34 ± 3.53%ID/g at 2 h postinjection). After coinjection with excess folic acid, the uptake in tumor and kidneys was significantly blocked. The results indicated that ^99mTcN‐pteroyl‐lys‐DTC was able to target the FR‐positive tumor cells and tissues specifically both in vitro and in vivo. Copyright © 2013 John Wiley & Sons, Ltd.     

Synthesis and biodistribution in mice of a new 99mTc nitrido complex for brain imaging

The bis(N‐cyclopentyl dithiocarbamato) nitrido technetium‐99m complex ^99mTcN(CPEDTC)₂ was synthesized by the reduction of ^99mTcO into [^99mTc≡N]²⁺ with stannous chloride in the presence of succinic dihydrazide and propylenediamine tetraacetic acid, followed by the addition of sodium N‐cyclopentyl dithiocarbamate monohydrate. The radiochemical purity (RCP) of the product was over 90% as measured by thin layer chromatography(TLC) and high performance liquid chromatography(HPLC). In vitro studies showed that the complex possessed good stability under physiological conditions. Its partition coefficient studies indicated it was a good lipophilic complex. The electrophoresis results showed the complex was neutral. The biodistribution results in mice indicated that ^99mTcN(CPEDTC)₂ was significantly retained into the brain. The brain uptake(ID%/g) was 3.58, 5.26, 3.73 and 2.72 and the brain/blood ratios were 0.79, 1.69, 1.59 and 1.58 at 5, 30, 60 and 90 min post‐injection, respectively. These results suggested potential usefulness of the complex as a new brain perfusion imaging agent. Copyright © 2004 John Wiley & Sons, Ltd.     

N‐[3‐[4‐(2‐methoxyphenyl) piperaziny‐1‐yl]propyl]cyclam: synthesized as a potential 5‐HT1A receptor ligand and labelled with 99mTc‐nitrido core

This paper reports the synthesis of new potential 5‐HT_1A receptor ligand N‐[3‐[4‐(2‐methoxyphenyl)piperaziny‐1‐yl]propyl]cyclam (MPPC) and radiolabelling of it with ^99mTc‐nitrido core. The novel neutral complex ^99mTcN‐MPPC combines 1,4,8,11‐tetraazacyclotetradecane (cyclam) ligand as chelate moiety for ^99mTc‐nitrido with a 1‐(2‐methoxyphenyl)piperazine moiety derived from WAY 100635 via a 3‐carbon alkyl chain. This provided a reliable and reproducible method for attaching the technetium to the pharmacophore moiety of WAY 100635. ^99mTcN‐MPPC was prepared by a two‐step procedure and the radiochemical purity was found to be greater than 95%. It was hydrophilic and stable for at least 4 h at room temperature. In vivo stability study in normal rats showed that no degradation of ^99mTcN‐MPPC was found in deproteinated blood samples at 2 h post‐injection. This effective ^99mTc‐labelling strategy for obtaining neutral ^99mTc nitrido complexes would be a useful tool to prepare new SPECT agents to image 5‐HT_1A receptor with cyclam conjugated ligands. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis,radiolabeling and evaluation of a new positively charged 99mTc‐labeled fatty acid derivative for myocardial imaging

¹²³I‐labeled fatty acids and ¹⁸F‐FDG are used as metabolic markers for detecting myocardial abnormalities. However, a ^99mTc‐based molecule may find wider application. In the present work, a new ^99mTc‐labeled, uni‐positively charged, 16‐carbon fatty acid has been prepared and evaluated in normal Swiss mice. The results are then compared with the neutral analogue reported earlier. A 16‐cysteinyl hexadecanoic acid conjugate was synthesized in a six‐step synthetic procedure starting with 16‐bromohexadecanoic acid. The ligand upon incubation with [^99mTcN(PNP6)]²⁺ core formed the required positively charged complex in ～85% yield. The complex, which was obtained as a mixture of syn‐anti isomers, was purified by HPLC and the major fraction was used for in vivo studies in Swiss mice. The biodistribution studies in Swiss mice showed initial uptake similar to ¹²⁵I‐IPPA followed by rapid clearance from the myocardium till 10 min p.i. Thereafter, the rate of clearance was significantly decreased, an observation reported earlier for positively charged fatty acid complexes. In terms of absolute uptake, the positively charged complex performed better than the neutral analogue reported earlier. The positively charged fatty acid complexes, prepared using [^99mTcN(PNP)]²⁺ core, seems to be better candidates for the development of myocardial metabolic tracers than their neutral counterparts. Copyright © 2010 John Wiley & Sons, Ltd.     

Solid phase preparations of 99mTc labeled radiopharmaceuticals

For the preparation of most ^99mTc radiopharmaceuticals, SnCl₂ has remained the agent of choice for reduction of Tc⁷⁺ to lower valency states, which facilitates its chelation by compounds of diagnostic importance. We have developed a simple technique in which SnCl₂ lyophilized in a glass vial, either alone or on a solid matrix of polymeric microspheres (beads), was used. Tin‐113 (t_1/2 – 115 d) was used as a tracer, which facilitated quantitative assessment of loss or release of tin in the reaction mixtures. The feasibility and efficacy of this technique were examined for preparations of four ^99mTc‐ labeled peptides, in which SnCl₂ was used as a reducing agent for radiolabeling, a procedure well established in our laboratory. Labeling efficiencies for all four peptides using SnCl₂ on solid phase was greater than 95%, as compared to less than 90% (P=0.05) for SnCl₂ lyophilized without the solid matrix. Colloid formation was less than 3% in either case. The stability of SnCl₂ was greater than six months for solid matrix, and less for that without the microspheres. The ¹¹³Sn measured as a daughter product ^113mIn indicated that release of SnCl₂ from microspheres in reaction mixture was 85±3%, as compared to 80±5% lyophilized alone. The recovery of ^99mTc in solution from microspheres was 95–100%. The large size of the microspheres used (649 μm) eliminated the risk of drawing them through a needle in a syringe used for injection of a preparation. Copyright © 2002 John Wiley & Sons, Ltd.     

Preparation and biological evaluation of 99mTcN‐4‐(cyclohexylpiperazin‐1‐yl)‐dithioformate as a potential sigma receptor imaging agent

The goal of this study is to develop a novel ^99mTc‐labeled σ receptor imaging agent. Potassium 4‐(cyclohexylpiperazin‐1‐yl)‐dithioformate, 2 , and the corresponding rhenium complex, ReN‐2 , were synthesized and characterized. ReN‐2 possessed moderate affinity toward σ₁ (K_i = 1.94 ± 0.60 µmol/L) and σ₂ (K_i = 2.83 ± 1.39 µmol/L) receptors. The radiolabeled complex ^99m TcN‐2 was prepared in high yield (> 95%) through the [^99mTcN] precursor and characterized by HPLC. ^99m TcN‐2 was found to be a lipophilic and neutral complex with good stability. The biodistribution in tumor‐bearing mice showed that ^99m TcN‐2 had good tumor uptake (2.12 ± 0.01 %ID/g at 2 h p.i.) and moderate brain uptake (0.27 ± 0.05 %ID/g at 2 h p.i.). After blocking with haloperidol, the uptakes by tumor and brain were lower than control. The results indicated that the complex has specific binding to the σ receptors in vivo. Further structural modifications of this complex are needed to obtain ^99mTc‐based σ receptor imaging agents with high affinity and subtype selectivity. Copyright © 2007 John Wiley & Sons, Ltd.     

Synthesis and biological evaluation of a novel asymmetrical 99mTc‐nitrido complex of metronidazole derivative

The novel dithiocarbamate derivative of metronidazole, potassium 2‐(2‐methyl‐5‐nitro‐1H‐imidazolyl)‐ethyl‐dithiocarbamate (MNIE‐DTC), was synthesized as the pharmacophore‐containing bifunctional ligand. The corresponding asymmetrical ^99mTc‐nitrido complex, expected as a tumor hypoxia marker, had been successfully obtained by the addition of the biphosphine ligand PNP5 (PNP5 = N‐ethoxethyl‐N,N‐bis[2‐(bis(3‐methoxypropyl)phosphino)ethyl]‐amine) and the dithiocarbamate ligand (MNIE‐DTC) to the ^99mTc‐nitrido precursor solution at 100°C for 15 min. The radiochemical purity of the product was above 95% as measured by thin‐layer chromatography and high‐performance liquid chromatography. In vitro studies showed that the complex possessed good stability under physiological conditions. Its partition coefficient studies indicated that it was a lipophilic complex. The electrophoresis results showed that the complex was cationic. Biological evaluation of the complex [^99mTcN(PNP5)(MNIE‐DTC)]⁺ performed in Kunming mice bearing H22 tumor showed that the complex had a moderate tumor uptake (0.57±0.06%ID/g at 1h), and the ratios of tumor/blood and tumor/muscle were 2.46 and 1.31 at 1h p.i., and reached 4.52 and 2.86 at 4h p.i., respectively. Copyright © 2007 John Wiley & Sons, Ltd.     

Evaluation of new positively charged 11‐ and 12‐carbon 99mTc‐labeled fatty acid derivatives for myocardial imaging

Radiolabeled fatty acids are used as tracers for myocardial metabolic imaging and currently ¹²³I‐iodophenyl pentadecanoic acid (IPPA) or ¹²³I‐β‐methyl‐iodophenyl pentadecanoic acid (BMIPP) are the agents of choice. However, ¹²³I being a cyclotron‐produced isotope, ^99mTc‐labeled fatty acids are more desirable substitutes to ¹²³I‐labeled fatty acids. Toward this, two fatty acids, having 11 and 12 carbon atoms respectively, modified with cysteine were synthesized in a four‐step procedure. These ligands were then radiolabeled with ^99mTc using the [^99mTcN(PNP6)]²⁺ core. Formation of the complexes and determination of radiochemical yields were ascertained by HPLC technique. In vivo distribution of the complexes was carried out in Swiss mice and the results are compared with ¹²⁵I‐IPPA. Both the complexes showed fast clearance from the myocardium till 10 min post injection (p.i.) followed by retention in the myocardium till 30 min p.i. However, compared with the result obtained with ¹²⁵I‐IPPA, the amount of activity retained in the myocardium by the present complexes were low. Both the complexes showed rapid clearance from liver, lungs, and blood unlike the case with ¹²⁵I‐IPPA. Copyright © 2010 John Wiley & Sons, Ltd.     

Radiochemical and biological characteristics of 99mTc‐difloxacin and 99mTc‐pefloxacin for detecting sites of infection

The optimization of the radiolabeling yield of ciprofloxacin analogous, difloxacin and pefloxacin, with ^99mTc was described. At pH 4, difloxacin was labeled with ^99mTc with a labeling yield of 95.6% by adding ^99mTc to 5 mg difloxacin in the presence of 100 µg SnCl₂·2H₂O whereas ^99mTc‐pefloxacin was labeled (98.1%) by adding ^99mTc to 4 mg pefloxacin in the presence of 50 µg SnCl₂·2H₂O. The radiochemical purity for both labeled compounds was evaluated with ITLC and HPLC system. Biological distribution of ^99mTc‐difloxacin and ^99mTc‐pefloxacin was carried out in experimentally induced infection rats, in the left thigh, using Staphylococcus aureus. Both thighs of the rats were dissected and counted and the ratio of bacterial infected thigh/contralateral thigh was then evaluated. T/NT for both ^99mTc‐difloxacin and ^99mTc‐pefloxacin was found to be 5.5±0.5 and 4.9±0.3, respectively, which was higher than that of the commercially available ^99mTc‐ciprofloxacin. Copyright © 2010 John Wiley & Sons, Ltd.     

Tissue compatibility and pharmacokinetics of three potential subcutaneous injectables for low‐pH drug solutions

Objectives The aim of the study was to investigate the tissue tolerance and bioavailability of four formulations containing 5% ricobendazole solubilised at low pH, following subcutaneous injection in sheep. Formulations were: a water‐in‐oil emulsion, a microemulsion, a hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD, 20%) drug solution, and a low‐pH drug solution (reference). Methods In‐vitro cytotoxicity of the formulations was investigated in L929 fibroblasts using MTS viability and lactate dehydrogenase leakage assays. Each formulation and respective vehicle was injected into either side of the back of a sheep to investigate the tissue tolerance and pharmacokinetics. Key findings In‐vitro studies suggested that both the emulsion and the microemulsion are unlikely to give a burst release of the low‐pH drug solution in aqueous media. The microemulsion showed the greatest in‐vitro cytotoxic effect but no significant difference was observed between the other formulations. In sheep, the three new formulations and vehicles caused little or no injection‐site reactions compared with a marked response to the reference formulation. Bioavailabilities of HP‐β‐CD formulation, emulsion and microemulsion formulations, relative to the reference formulation, were 194, 155 and 115%, respectively. Conclusions The three new subcutaneous injectables showed promise for reducing irritation of low‐pH solubilised ricobendazole. HP‐β‐CD significantly enhanced the drug absorption. Controlling the burst release of the low‐pH drug solution may improve tissue tolerance and minimise post‐injection precipitation, and hence increase drug bioavailability. The in‐vitro cytotoxicity studies did not predict the in‐vivo irritation effects.     

Lactosaminated N‐succinyl‐chitosan as a liver‐targeted carrier of 99mTc in vivo for nuclear imaging and biodistribution

Lactosaminated N‐succinyl‐chitosan (LNSC), a water‐soluble biodegradable derivative of chitosan, was prepared, characterized, and investigated for nuclear imaging and body distribution. The labeling efficiency of LNSC was examined with ^99mTc, and the obtained complex was used as liver‐targeted delivery system in vivo for nuclear imaging, and its biodistribution within the body was studied. The labeling efficiency with ^99mTc was investigated for time of reaction, effect of substrate amount, effect of stannous chloride (SnCl₂) concentration, and effect of the pH of the reaction mixture, in order to approach the optimum condition for labeling technique. It was found that the maximum yield for labeling of 2.5‐mg ^99mTc‐LNSC was 96.9% when 50 µg of SnCl₂ was used at pH 3.5–5, at room temperature and 5‐min reaction time. An in vivo biodistribution study of radiolabeled LNSC was carried out in female Wistar rats, and the body distribution profile was recorded by gamma scintigraphy. The biodistribution of ^99mTc‐labeled LNSC (^99mTc‐LNSC) in each organ was calculated as a percentage of the injected dose per gram of tissue (%ID/g). ^99mTc‐LNSC was shown to be a highly potential approach for liver imaging. Moreover, the rapid excretion of LNSC through the kidneys suggests that water‐soluble chitosan derivatives are good carriers of radioactive elements that do not accumulate in the body. The results indicate that the easy and inexpensive extraction, and thus the ready availability, of chitosan and its derivatives makes them potentially useful for applications in scintigraphic imaging.     

A study of radiogallium aqueous chemistry: in vitro and in vivo characterisation of 67Ga‐hydrolysed‐stannous fluoride particles

The objective of this study was to explore the aqueous chemistry of gallium using ⁶⁷Ga‐chloride starting material, by radiolabelling hydrolysed(h)‐stannous fluoride particles and then characterising the optimal formulation for radiochemical purity (RCP) and radioactive particle size distribution in vitro. The pilot reactions determined stannous fluoride was added to ⁶⁷Ga‐acetate under nitrogen and then heated at 100 °C for 20 min to achieve ≥95% RCP and ⁶⁷Ga‐particles were >3 µm in diameter. A high radioactive concentration of ⁶⁷Ga‐h‐SnF₂ particles could be prepared similarly in ≥97% RCP with 74% as 3–5 µm and 26% >5 µm in diameter. The latter formulation had larger particles than ^99mTc‐h‐SnF₂ colloid (96% of 1–3 µm), and it resulted in a rat biodistribution of 41% in the lungs, 41% in the liver plus spleen and 18% in the carcass at 20 min after injection. The carcass activity was attributed to bone marrow and some ⁶⁷Ga‐transferrin formed in blood. Isolated mixed human leucocytes were radiolabelled with ⁶⁷Ga‐h‐SnF₂ particles in 100% efficiency, and the ⁶⁷Ga‐cells did not release soluble ⁶⁷Ga³⁺ at room temperature over 3 h. The ⁶⁷Ga‐h‐SnF₂ particle formulation could find a use in labelling leucocyte cells for in vivo homing studies when delayed animal imaging is required.     

Synthesis and characterization of new 99mTc‐radiopharmaceuticals with dithiobenzoate derivatives for the study of septic inflammatory processes

Improved methods for the preparation of ^99mTc‐radiopharmaceuticals containing dithiobenzoate ligands, in sterile and pyrogen free conditions, are described. These procedures are based on the reaction of these ligands either with [^99mTc] pertechnetate in the presence of a strong reducing agent (HCl/tertiary phosphine, SnCl₂·2H₂O), or with pre‐reduced complexes obtained from different kit formulations. All the preparations led to the high‐yield formation of the neutral and lipophilic ^99mTc‐complex [^99mTc][Tc(S₃CPh)₂(S₂CPh)], which is analogous to the corresponding compounds obtained with rhenium and the long‐lived β‐emitting isotope technetium‐99 g recently described. HPLC analysis and thin layer chromatography were used to confirm the characterisation of the resulting ^99mTc‐radiopharmaceutical which was found to be potentially suitable for blood‐cell labelling as applied to the diagnosis of inflammatory processes. Copyright © 2003 John Wiley & Sons, Ltd.     

Non-inclusion complexes between riboflavin and cyclodextrins

Objectives To investigate the molecular interaction between β‐cyclodextrin (βCD) or hydroxypropyl‐β‐cyclodextrin (HPβCD) and riboflavin (RF), and to test the anticancer potential of these formulations. Methods The physicochemical characterization of the association between RF and CDs was performed by UV‐vis absorption, fluorescence, differential scanning calorimetry and NMR techniques. Molecular dynamics simulation was used to shed light on the mechanism of interaction of RF and CDs. Additionally, in‐vitro cell culture tests were performed to evaluate the cytotoxicity of the RF–CD complexes against prostate cancer cells. Key findings Neither βCD nor HPβCD led to substantial changes in the physicochemical properties of RF (with the exception of solubility). Additionally, rotating frame Overhauser effect spectroscopy experiments detected no spatial correlations between hydrogens from the internal cavity of CDs and RF, while molecular dynamics simulations revealed ‘out‐of‐ring’ RF–CD interactions. Notwithstanding, both RF–βCD and RF–HPβCD complexes were cytotoxic to PC3 prostate cancer cells. Conclusions The interaction between RF and either βCD or HPβCD, at low concentrations, seems to be made through hydrogen bonding between the flavonoid and the external rim of both CDs. Regardless of the mechanism of complexation, our findings indicate that RF–CD complexes significantly increase RF solubility and potentiate its antitumour effect.     

Synthesis and evaluation of a novel 99mTc nitrido radiopharmaceutical with alendronate dithiocarbamate as a potential bone‐imaging agent

Currently, a popular strategy for designing novel radioprobes as bone‐imaging agents is based on the concept of bifunctional radiopharmaceuticals. Considering the dithiocarbamate ligand can act as a suitable bifunctional linking agent to attach technetium‐99m (^99mTc) to corresponding target molecules, in this study, alendronate dithiocarbamate (ALNDTC) was synthesized and radiolabeled with [^99mTc≡N]²⁺ core by ligand exchange reaction to produce ^99mTcN‐ALNDTC complex, for the potential use as a novel probe for bone imaging. The radiochemical purity of the complex was over 90%. The complex was stable in vitro and could bind to hydroxyapatite. The partition coefficient result indicated it was hydrophilic, and an evaluation of biodistribution in mice indicated that the complex exhibited a higher bone uptake than did ^99mTc‐labeled methylenediphosphonate (^99mTc‐MDP). Further, single photon emission computed tomography imaging study indicated clear accumulation in bone, suggesting that ^99mTcN‐ALNDTC would be a promising candidate for bone imaging.     

Synthesis and bio evaluation of a new fatty acid derivative labelled with technetium‐99m

¹²³I‐iodophenylpentadecanoic acid (IPPA) and ¹²³I‐beta‐methyliodophenylpentadecanoic acid (BMIPP) are radiolabelled fatty acid derivatives used for assessment of myocardial viability. Because of limited accessibility of ¹²³I in the clinical scenario, a 99m‐technetium‐based agent would be more advantageous. In this context, a xanthate derivative of 15‐hydroxypentadecanoic acid (HPDA) was synthesized for radiolabelling with [^99mTcN]²⁺ intermediate. Direct reaction of the HPDA with carbon disulphide in presence of crushed sodium hydroxide in dry tetrahydrofuran resulted in moderate yield of the desired xanthate product. The prepared ligand was radiolabelled with [^99mTcN]²⁺ intermediate and the resultant complex was characterized by paper electrophoresis and HPLC. The labelled preparation was assessed for its myocardial extraction and retention characteristics using Swiss mice model. The HPDA xanthate derivative was obtained in a low yield of ～30%. Labelling via the [^99mTcN]²⁺intermediate gave more than 95% complexation. During in vivo studies with the [TcN]²⁺ labelled complex maximum heart uptake observed was 3.10%ID/g at 5 min p.i., which cleared out rapidly, with retention of 0.79%ID/g of the activity at 60 min p.i. The ^99mTcN‐HPDA xanthate derivative showed some uptake in the heart but rapid wash out and substantial uptake in the background organs (blood, liver and lungs) led to unfavourable critical ratios at all the time points of study. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis and biodistribution of novel 99mTc‐nitrido methylpiperidine dithioformate derivatives as potential brain imaging agents

Three dithioformate ligands with methyl substituted on the piperidine rings, potassium 1‐(2‐methylpiperidine‐1‐yl)‐dithioformate (2‐mp), potassium 1‐(3‐methylpiperidine‐1‐yl)‐dithioformate (3‐mp) and potassium 1‐(4‐methylpiperidine‐1‐yl)‐dithioformate (4‐mp) were synthesized. The corresponding ^99mTc‐nitrido complexes were prepared in high yield (>95%) through the [^99mTcN] intermediate and characterized by thin layer chromatography and high‐performance liquid chromatography. All the neutral ^99mTc‐nitrido complexes were stable under physiological conditions and lipophilic with log P values between 1.40 and 1.58. In vivo biodistribution results showed that all the ^99mTc‐nitrido complexes displayed high brain uptakes and long retention times. Among them, ^99mTcN‐4mp, demonstrated the best properties for brain imaging with the brain uptake 3.40±0.24, 3.22±0.31, 2.72±0.28 and 2.22±0.18% ID/g at 5, 30, 60 and 120 min p.i., respectively. Moreover, the influence of stereochemistry of the ^99mTcN complexes with methyl substitution on ortho, meta and para positions on piperidine ring on the biodistribution properties were investigated with B3LYP/6‐31G*(LANL2DZ for Tc) method using the Gaussian 03 program package. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis,radio‐LC–MS analysis and biodistribution in mice of 99mTc–NIM–BAT

S,S′‐bis‐trityl‐N‐BOC‐1,2‐ethylenedicysteamine (S,S′‐bis‐trityl‐N‐BOC–BAT) was conjugated to 2‐nitroimidazole (NIM) through a propylene spacer in order to provide a precursor for a potential technetium‐99 m labelled hypoxia tracer. For labelling with technetium‐99 m, a two‐step one‐pot procedure was developed consisting of deprotection of the ligand by heating in mild acidic conditions and subsequent exchange labelling in the presence of SnCl₂, tartrate and ^99mTcO. The labelling reaction mixture was analyzed using electrospray radio‐LC–MS and the observed mass spectrum corresponding to the main radiometric peak was in accordance with the predicted structure of oxo–Tc(V)–NIM–BAT. ^99mTc–NIM–BAT was purified using RP–HPLC and its biodistribution was evaluated in normal mice at 10 min and 4 h p.i. ^99mTc–NIM–BAT was cleared from plasma mainly by hepatobiliary excretion. Copyright © 2003 John Wiley & Sons, Ltd.     

Oral bioavailability of a poorly aqueous drug from three different SBE7-β-cyclodextrin based formulations in beagle dogs

Oral administration of Lu 35-138, a low aqueous soluble compound, was investigated in three different formulations containing sulfobutylether β-cyclodextrin (SBE₇βCD) in fasted beagle dogs. The evaluated formulations was (i) a SBE₇βCD solution, (ii) a spray dried solution filled into hard gelatine capsules, and (iii) a direct compressible tablet containing SBE₇βCD. The three formulations did not lead any significant differences in the obtained AUCs, though a trend was observed for the highest absorption when Lu 35-138 was dosed in the cyclodextrin solution. These results demonstrate that a solid formulation with a relative low content of cyclodextrins can be used to increase the bioavailability of a low water soluble compound to a relative high level when compared to a cyclodextrin solution.