Nitrido Technetium-99m Research Articles

Synthesis and biodistribution of a novel 99mTc nitrido dithiocarbamate complex containing aromatic group for cerebral imaging

In the present study, the N-benzyl dithiocarbamate (BZDTC) was synthesized and radiolabeled with [ 99mTcN] 2+ intermediate to form the bis(N-benzyl dithiocarbamato) nitrido technetium-99m complex [ 99mTcN(BZDTC) 2]. The radiochemical purity of the complex was over 90% by thin layer chromatography (TLC) and high performance liquid chromatography (HPLC). It was stable over 6 h at room temperature. The partition coefficient and electrophoresis results indicated that this complex was lipophilic and neutral. Biodistribution in mice showed that the complex accumulated in the brain with high uptake. The brain uptake (ID%/g) was 1.87, 1.21 and 0.85 and the brain/blood ratio was 0.75, 1.55 and 1.12 at 5, 30 and 60 min post-injection, respectively. These results suggest that this complex could be a potential brain perfusion imaging agent.

Synthesis and biodistribution of two novel 99mTc nitrido dithiocarbamate complexes containing heterocyclic linkage as potential brain perfusion imaging agents

In the present study, two novel 99mTc nitrido dithiocarbamate complexes containing heterocyclic linkage, the bis(N-2-(1-piperidyl)ethyl dithiocarbamato) nitrido technetium-99m complex 99mTcN(PPEDTC)2 and bis(N-2-(1-pyrrolidino)ethyl dithiocarbamato) nitrido technetium-99m complex 99mTcN(PREDTC)2 have 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 ligands. The radiochemical purity of the complexes were over 90% as measured by thin layer chromatography (TLC). In vitro studies showed that the complexes possessed good stability. Their partition coefficients indicated that they were lipophilic complexes. Biodistribution in mice showed that the 99mTcN(PPEDTC)2 complex accumulated in brain with high uptake and good retention. As compared with the 99mTcN(PREDTC)2 complex, the former showed much higher brain uptake than the latter.

Synthesis of a bis-(N-sec-butyl-dithiocarbamato)-nitrido-99mTc complex: a potential new radiopharmaceutical for brain perfusion studies

A bis-(N-sec-butyl dithiocarbamato) nitrido technetium-99m complex [99mTcN(SBDTC)2] (SBDTC: N-sec-butyl dithiocarbamato) was synthesized by the reduction of 99mTcO4− to [99mTc≡N]2+ with stannous chloride in the presence of succinic dihydrazide and propylenediamine tetraacetic acid, followed by the addition of sodium N-sec-butyl dithiocarbamate dihydrate. The radiochemical purity of the complex was over 90% as measured by thin layer chromatography. It was stable over 6h at room temperature. Its partition coefficient indicated that it was a good lipophilic complex. The electrophoresis results showed that the complex was neutral. Biodistribution studies in mice demonstrated that the complex accumulated in the brain with high uptake and good retention. The brain uptake (ID%/g) was 3.89, 3.44 and 2.82 and the brain/blood ratio was 1.41, 1.45, 1.00 at 5, 30 and 60min post-injection respectively. These results suggested the potential usefulness of the complex as a brain perfusion imaging agent.

Synthesis and biodistribution of99mTcN(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 99mTcO4- 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.

Asymmetrical nitrido tc-99m heterocomplexes as potential imaging agents for benzodiazepine receptors.

The design, synthesis, and biological evaluation of nitrido technetium-99m complexes for imaging benzodiazepine receptors are described. The design was performed by selecting the precursor biologically active substrate desmethyldiazepam, and the reactive metal-containing fragment [(99m)Tc(N)(PXP)](2+) (PXP = diphosphine ligand) as molecular building-blocks for assembling the structure of the final radiopharmaceuticals through the application of the so-called 'bifunctional' and 'integrated' approaches. This required the synthesis of the ligands H(2)BZ1, H(2)C1, and H(2)C2 (Figures 1 and 2) derived from desmethyldiazepam. In turn, these ligands were reacted with [(99m)Tc(N)(PXP)](2+) to afford the complexes [(99m)Tc(N)(PXP)(L)] (L = BZ1, C1, C2). The chemical nature of the resulting Tc-99m radiopharmaceuticals was investigated using chromatographic methods, and by comparison with the analogous complexes prepared with the long-lived isotope Tc-99g and characterized by spectroscopic and analytical methods. Results showed that the complexes [(99m)Tc(N)(PXP)(L)] are neutral and possess an asymmetrical five-coordinated structure in which two different bidentate ligands, PXP and L, are coordinated to the same Tc[triple bond]N core. With the ligand H(2)BZ1, two isomers were obtained depending on the syn or anti orientation of the pendant benzodiazepine group relative to the Tc[triple bond]N multiple bond. Biodistribution studies of Tc-99m complexes were carried out in rats, and affinity for benzodiazepine receptors was assessed through in vitro binding experiments on isolated rat's cerebral membranes using the corresponding Tc-99g complexes.

Technetium-99m nitrido radiopharmaceuticals with unprecedented biological properties

The chemical methods for the production of technetium-99m radiopharmaceuticals containing a terminal Tc<FONT FACE=Symbol>º</FONT>N triple bond have been established more than a decade ago. From that time, the chemistry of nitrido Tc-99m complexes has provided a highly efficient tool for the design and preparation of novel classes of diagnostic agents, and a number of potentially useful radiopharmaceuticals have been discovered. In particular, nitrido technetium-99m tracers have been developed for heart perfusion imaging. In this short review, the chemical and biological properties of the neutral myocardial perfusion tracer bis(N-ethoxy, N-ethyl-dithiocarbamato) nitrido Tc-99m (TcN-NOEt) will be summarized along with the preparation and preliminary biological evaluation of the first class of monocationic nitrido technetium-99m radiopharmaceuticals exhibiting improved biodistribution properties closer to those expected for an ideal perfusion imaging agent.

Synthesis and biodistribution of a new 99mTc nitrido complex for cerebral imaging

The bis(N-isopentyl dithiocarbamato) nitrido technetium-99m complex [ 99mTcN(IPEDTC) 2] (IPEDTC: N-isopentyl dithiocarbamato) has been synthesized by the reduction of 99mTcO 4 − into [ 99mTcN] 2+ with stannous chloride in the presence of succinic dihydrazide and propylenediamine tetraacetic acid, followed by the addition of the sodium salt of N-isopentyl dithiocarbamate. The radiochemical purity of the complex was over 90% as measured by thin layer chromatography. In vitro studies showed that the complex possessed good stability under physiological conditions. Its partition coefficient indicated that it was a lipophilic complex. The electrophoresis results showed the complex was neutral. Biodistribution in mice showed that the complex accumulated in brain with high uptake and good retention. The brain uptake (ID%/g) was 2.22, 2.06 and 2.45 and the brain/blood ratio was 1.01, 2.34 and 3.22 at 5, 30 and 60 min post-injection, respectively. These results for the complex suggested that it could be a potential brain perfusion imaging agent.

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.

Synthesis and biodistribution of a new 99mTc nitrido complex as a potential myocardial and cerebral imaging agent

The bis( N-methyl, N-cyclohexyl dithiocarbamato) nitrido technetium-99m complex [ 99mTcN(MECHDTC) 2] (MECHDTC: N-methyl, N-cyclohexyl dithiocarbamato) has been synthesized through a ligand-exchange reaction. The two-step procedure consisted of an initial reaction of 99mTcO 4 − with succinic dihydrazide in the presence of stannous chloride as reducing agent and propylenediamine tetraacetic acid as complexant, and successive addition of sodium salt of N-methyl, N-cyclohexyl dithiocarbamate. 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 6 h. Its partition coefficient indicated that it was a lipophilic complex. The electrophoresis results showed that the complex was neutral. Biodistribution in mice showed that the complex accumulated in the heart and brain with high uptake. The heart/blood, heart/lung and brain/blood ratios were 5.55, 2.11 and 1.10, respectively, at 30 min post-injection, suggesting that this compound is a potential myocardial and cerebral imaging agent.

Preparation of 99mTcN(CBDTC)2 and its biodistribution in mice

In order to seek a new class of brain perfusion imaging agent containing [99mTcN]2+ core, bis(N-cyclobutyl dithiocarbamato) nitrido technetium-99m complex [99mTcN(CBDTC)2] (CBDTC: N-cyclobutyl dithiocarbamato) was synthesized through a simple and efficient method, which can be utilized for the preparation of a radiopharmaceutical through a lyophilized kit formulation. 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 6h. It's partition coefficient indicated that it is a good lipophilic complex. Biodistribution in mice showed that the complex was significantly retained in the brain. The brain uptake (ID %/g) was 3.61, 3.15 and 2.62 and the brain/blood ratio was 1.00, 1.44 and 1.30 at 5, 30 and 60min post-injection, respectively. These results suggest that this compound could be a potential brain perfusion imaging agent.

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

Bis( N-isobutyl-dithiocarbamato) nitrido technetium-99m complex [ 99mTcN(IBDTC) 2] (IBDTC: N-isobutyl dithiocarbamato) was synthesized by the reduction of 99mTcO 4 − into [ 99mTc≡N] 2+ with stannous chloride in the presence of succinic dihydrazide and propylenediamine tetraacetic acid, followed by the addition of sodium N-isobutyl dithiocarbamate dihydrate. The radiochemical purity of the complex was over 90% as measured by thin layer chromatography. It was stable over 6 h at room temperature. Its partition coefficient indicated that it is a good lipophilic complex. Biodistribution in mice demonstrated that the complex accumulated in the brain with high uptake and good retention. The brain uptake (ID%/g) was 6.22, 5.45 and 3.88 and the brain/blood ratio was 1.51, 2.24, 1.84 at 5, 30 and 60 min post-injection, respectively. These results suggest potential usefulness of the complex as a brain perfusion imaging agent.

Synthesis of 99m TcN(IPDTC)2 and its biodistribution in mice

In order to seek a new class of brain perfusion imaging agent containing[ 99m TcN]2+ core, the bis(N-isopropyl dithiocarbamato)nitrido technetium-99m complex [ 99m TcN(IPDTC)2 ] (IPDTC:N-isopropyldithiocarbamato) has been synthesized through a simple and efficient method,which can be utilized for the preparation of a radiopharmaceutical througha lyophilized formulation. The radiochemical purity of the complex was over90% determined by thin layer chromatography. No decomposition of the complexwas observed at room temperature over a period of 12 hours. Its partitioncoefficient indicated that it was a good lipophilic complex. Biodistributionin mice demonstrated that the complex was significantly retained into thebrain. The brain uptake (ID%/g) was 3.90, 2.67 and 1.54 and the brain/bloodratios were 1.26, 1.06 and 0.85 at 5, 30 and 60-minute post-injection, respectively.The results showed that the complex may lead to a further development of theradiopharmaceutical as a brain perfusion tracer.

Optimal timing for initial and redistribution technetium 99m-N-NOET image acquisition

Background. Bis (N-ethoxy, N-ethyl dithiocarbamato) nitrido technetium-99m (V) (Tc-99m-N-NOET) is a new Tc-99m-labeled myocardial perfusion imaging agent that redistributes. We sought to determine the optimal timing for acquiring initial and delayed images to maximize sensitivity for the detection of coronary stenoses. Methods. Twelve anesthetized dogs with critical stenoses of the left anterior descending coronary artery were infused with adenosine (250 μg/kg/min) or MRE-0470, an adenosine A 2a agonist (0.6 μg/kg/min × 10 minutes), and Tc-99m-N-NOET (8 mCi; 296 MBq) was injected intravenously at peak flow. Myocardial and lung Tc-99m-N-NOET activities were determined by serial quantitative imaging and arterial blood sampling was performed over 2 hours. Results. Left anterior descending/left circumflex artery defect count ratios showed rapid redistribution during the first 10 minutes after Tc-99m-N-NOET injection (0.66 ± 0.02 at 2 minutes to 0.73 ± 0.01 at 10 minutes; P < .01). Redistribution was nearly complete by 120 minutes (defect ratio = 0.87 ± 0.03; P ≤ .01 vs 2 minutes). Lung activity fell significantly during the first 10 minutes from a heart/lung activity ratio of 1.07 ± 0.05 (2 minutes) to 1.44 ± 0.09 (10 minutes; P <- . O1). Conclusion. Initial stress Tc-99m-N-NOET images should be acquired within 10 minutes after injection, whereas delayed images can be obtained as early as 2 hours later. Lung activity clears rapidly, permitting acquisition of good-quality poststress cardiac images. These Tc-99m-N-NOET uptake and redistribution kinetics after vasodilator stress provide important information for designing clinical imaging protocols for optimal identification of inducible ischemia.

Synthesis, characterization and biodistribution of a99mTc nitrido complex as a potential brain perfusion imaging agent

The bis(N-cyclohexyl-dithiocarbamato) nitrido technetium-99m complex [99mTcN-(CHDTC)2] (CHDTC:N-cyclohexyl dithiocarbamato) has been synthesized through a ligand-exchange reaction. The two-step procedure involved the initial reaction of 99mTcO−4 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 sodium N-cyclohexyl dithiocarbamate dihydrate. The radiochemical purity of the complex was over 90% by thin layer chromatography. It was stable over 6 h at room temperature. Its partition coefficient indicated that it was a good lipophilic complex. Biodistribution in mice demonstrated that the complex accumulated in brain with high uptake and good retention. The brain uptake (ID%/g) was 2.91, 5.88 and 5.91 at 5,30 and 60 min post-injection respectively. The ratio of brain/blood in mice was high, 2.10 at 1 h post-injection. The results for the complex suggested that it could be a potential brain perfusion imaging agent. Copyright © 2000 John Wiley & Sons, Ltd.

The effect of ischemic injury on the cardiac transport of Tc-99m N-NOET in the isolated rabbit heart

Background. Bis (N-ethoxy, N-ethyl dithiocarbamato) nitrido technetium-99m (V) (TcN-NOET) is a neutral lipophilic myocardial perfusion agent. The effect of ischemic injury on the cardiac transport of TcN-NOET and thallium-201 was determined in isolated rabbit hearts. Methods and Results. The multiple indicator dilution method was used to determine the maximum (E max) and net extraction (E net, at 5 minutes) of TcN-NOET and Tl-201 at control and after 10 minutes (n = 4) or 45 minutes (n = 4) of no-flow ischemia. After 10 minutes of ischemia the mean E max for Tl-201 was unchanged, 0.86 ± 0.03 vs 0.85 ± 0.02, whereas Tl-201 E net showed a small decrease from 0.46 ± 0.03 to 0.40 ± 0.03, P < .001. Forty-five minutes of ischemia mildly reduced E max for Tl-201 (0.87 ± 0.04 to 0.74 ± 0.04, P < .001) and severely reduced E net (0.46 ± 0.03 vs 0.16 ± 0.04, P < .001). Neither E max nor E net for TcN-NOET was significantly affected by 10 minutes of ischemia (0.54 ± 0.04 vs 0.58 ± 0.03 and 0.24 ± 0.04 vs 0.26 ± 0.04, respectively). However, severe ischemic injury caused significant reductions versus control in both E max (0.59 ± 0.06 vs 0.42 ± 0.05, P < .001) and E net (0.27 ± 0.03 vs 0.18 ± 0.05, P < .01). Conclusions. TcN-NOET is a new myocardial perfusion agent with moderate myocardial extraction. Although less sensitive than Tl-201 to mild ischemic injury, TcN-NOET extraction and retention are decreased by severe ischemic injury, making uptake of TcN-NOET a possible marker of myocardial viability.

Synthesis and biodistribution of nitrido technetium-99m radiopharmaceuticals with dithiophosphinate ligands: a class of brain imaging agents

The symmetrical complexes [ 99mTc][TcN(R 2PS 2) 2] [R CH 3, CH 2CH 3, CH 2CH 2CH 3, CH 2(CH 3) 2], and the unsymmetrical complex [ 99mTc][TcN(Me 2PS 2)(Et 2PS 2)] have been prepared, at tracer level, through a two-step procedure involving the preliminary formation of a prereduced technetium nitrido intermediate followed by substitution reaction onto this species by the appropriate dithiophosphinate ligand [R 2PS 2]Na. The chemical identity of the resulting complexes have been established by comparison with the corresponding 99Tc-analogs prepared, at macroscopic level, by reacting the complex [ 99TcNCl 4] [ n-Bu 4N] ( n-Bu = n-butyl) with an excess of ligand in methanol, and characterized by elemental analyses and spectroscopic techniques. The complexes are neutral and lipophilic, and possess a square pyramidal geometry, with an apical Tc N group and two dithiophosphinate ligands spanning the four positions on the basal plane through the four sulfur atoms of the >PS 2 group. In vitro studies showed that these radiopharmaceuticals are stable in solution and that their chemical identity was not altered after incubation with rat blood. Biodistribution studies have been carried out in rats and primates. The results demonstrate that these compounds are significantly retained into the brain of these animals for a prolonged time. Planar gamma camera images have been obtained in monkeys showing a good visualization of the cerebral region. However, the existence of persistent blood activity yields a brain/blood ratio lower than that observed with other 99mTc-based brain perfusion imaging agents.