99mTc-nitrido Complexes Research Articles

99mTc labelled complexes with secnidazole xanthate: Synthesis and evaluation as potential radiotracers to target tumor hypoxia

In this study, the commercially available secnidazole was successfully converted to secnidazole xanthate (SNXT), in which the xanthate group can act as a bifunctional chelator to coordinate with 99mTc. 99mTc-nitrido complex of SNXT(99mTcN-SNXT) and 99mTc-oxo complex of SNXT(99mTcO-SNXT) were prepared with high radiochemical purity. Both of the complexes were found to be stable in vitro and to exhibit similar hydrophilicity. In addition, comparative in vitro cell uptake studies under anoxic and normoxic conditions demonstrated that both agents were preferentially taken up by hypoxic cells. Biodistribution studies in mice bearing S180 tumor showed 99mTcO-SNXT exhibited a higher tumor uptake and tumor-to-muscle ratio than 99mTcN-SNXT. Furthermore, in SPECT imaging study, 99mTcO-SNXT exhibited a clear accumulation in tumor at 2 h post-injection, suggesting its potential to be a novel hypoxia imaging agent.

Synthesis and biological evaluation of novel 99mTc-oxo and 99mTc-nitrido complexes with phenylalanine dithiocarbamate for tumor imaging

In this study, phenylalanine dithiocarbamate (PHEDTC) ligand was successfully synthesized and then radiolabeled with [99mTcO]3+ core and [99mTc≡N]2+ core to produce 99mTcO–PHEDTC and 99mTcN–PHEDTC, respectively. Both complexes were prepared with high radiochemical purity and had good stability. The partition coefficient results showed they were hydrophilic, while 99mTcN–PHEDTC was more hydrophilic than 99mTcO–PHEDTC. The biodistribution study in mice bearing S 180 tumor showed that 99mTcO–PHEDTC and 99mTcN–PHEDTC had high tumor uptake at 2 h post-injection, 1.91 and 1.21, respectively. The good uptake and retention in tumor together with favorable tumor-to-muscle ratios make them promising candidates for further evaluation as potential tumor imaging agents.

The Missed Tc-99m Radiopharmaceuticals for Cardiac Imaging

Despite the success of 99mTc-sestamibi and 99mTc-tetrofosmin, the search for 99mTc heart imaging agents having a pharmacokinetic behavior much closer to that of an ideal perfusion tracer has been never interrupted. This short review illustrates advances in this field that have been made using the class of 99mTc complexes characterized by the presence of a terminal technetium-nitrogen multiple bond. This category of 99mTc compounds has proven to be particularly useful for cardiac imaging and a number of highly interesting compounds have been developed. The main chemical and biological properties of these agents are briefly summarized here. Keywords: Myocardial imaging, Myocardial perfusion, 99mTc nitrido complexes, SPECT

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

AbstractThis paper reports the synthesis of new potential 5‐HT1A 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‐HT1A receptor with cyclam conjugated ligands. Copyright © 2008 John Wiley & Sons, Ltd.

Avidin–biotin system: a small library of cysteine biotinylated derivatives designed for the [99mTc(N)(PNP)]2+ metal fragment

Using the avidin-biotin system as model, we investigate here the effective application of [Tc(N)L(PNP)](+/0) technology (L=N-functionalized cysteine [O(-),S(-)]; PNP=aminodiphosphine) to the preparation of target-specific radiopharmaceuticals. A series of (99m)Tc-nitrido complexes containing functionalized biotin ligands was prepared and their biological profile was determined. To minimize the steric and the electronic influences of the Tc-carrying complex on the biotin-avidin receptor interaction, the following N-functionalized cysteine-biotin derivatives were synthesized: (1) Biot-CysOSH; (2) Biot-Abu-CysOSH; (3) Biot-Abz-CysOSH; (4) Biot-l-(Ac)Lys-CysOSH; (5) Biot-d-(Ac)Lys-CysOSH; (6) Biot-Glu-CysOSH. The asymmetrical nitrido-Tc(V) (99g/99m)Tc(N)(Biot-X-CysOS)(PNP3) (X=spacer) complexes, where PNP3 was N,N-bis-[(dimethoxypropyl)phosphinoethyl] methoxy-ethylamine, were obtained by simultaneous addition of PNP3 and the relevant biotinylated ligand to a solution containing a (99m)Tc-nitrido precursor (yields >95%). In all cases, a mixture of syn- and anti isomers was observed. In vitro challenge experiments with glutathione and cysteine indicated that no transchelation reactions occurred. Assessment of the in vitro binding to avidin of the complexes revealed that only the complexes containing Biot-Abu-CysOS and Biot-Glu-CysOS ligand maintained a good affinity for the concentrator. Stability studies carried out in human and mouse plasma as well as in rat and mouse liver homogenate evidenced a rapid enzymatic degradation for the (99m)Tc(N)(Biot-Abu-CysOS)(PNP3) complex, whereas the (99m)Tc(N)(Biot-Glu-CysOS)(PNP3) one was stable in all conditions. Tissue biodistribution in normal Balb/C mice of the most stable candidate showed a rapid clearance both from the blood and the other tissues. The activity was eliminated both through the hepatobiliary system and the urinary tract.

Impact of Bidentate Chelators on Lipophilicity, Stability, and Biodistribution Characteristics of Cationic 99mTc-Nitrido Complexes

This report describes synthesis and evaluation of novel cationic 99mTc-nitrido complexes, [99mTcN(L)(PNP)](+) (L = ma, ema, tma, etma and mpo; PNP = PNP5, PNP6, and L6), as potential radiotracers for heart imaging. Cationic complexes [99mTcN(L)(PNP)](+) were prepared in two steps. For example, reaction of succinic dihydrazide with 99mTcO4(-) in the presence of excess stannous chloride and PDTA resulted in the [99mTcN(PDTA)n] intermediate, which then reacted Hmpo and PNP6 at 100 degrees C for 10-15 min to give [99mTcN(mpo)(PNP6)](+) in >90% yield. It was found that bidentate chelators have a significant impact on lipophilicity, solution stability, biodistribution, and metabolic stability of cationic 99mTc-nitrido complexes. The fact that [99mTcN(ema)(PNP6)](+) decomposes rapidly in the presence of cysteine (1 mg/mL) while [99mTcN(etma)(PNP6)](+) and [99mTcN(mpo)(PNP6)](+) remain stable for >6 h under the same conditions strongly suggests that thione-S donors in bidentate chelators increase the solution stability of their cationic 99mTc-nitrido complexes. Biodistribution studies were performed on four cationic 99mTc-nitrido complexes in Sprague-Dawley rats. [99mTcN(etma)(PNP5)](+) is of particular interest due to its high initial heart uptake (1.81 +/- 0.35 %ID/g at 5 min postinjection), and long myocardial retention (1.99 +/- 0.47 %ID/g at 120 min postinjection). The heart/liver ratio of [99mTcN(etma)(PNP5)](+) (6.06 +/- 1.48) at 30 min postinjection is almost identical that of 99mTcN-DBODC5 (6.01 +/- 1.45), and is >2 times better than that of 99mTc-sestamibi (2.90 +/- 0.22). Results from metabolism studies show that [99mTcN(etma)(PNP5)](+) has no significant metabolism in the urine, but it does show significant metabolism in feces samples at 120 min postinjection. Planar imaging studies suggest that [99mTcN(etma)(PNP5)](+) might be able to give clinically useful images of the heart as early as 30 min postinjection. [99mTcN(etma)(PNP5)](+) is a very promising candidate for more preclinical evaluations in various animal models.

99mTc-labeled annexin V fragments: a potential SPECT radiopharmaceutical for imaging cell death

Annexin V is a protein that binds to phosphatidylserine exposed on dying cells. The phosphatidylserine-specific sequence is attributed to a chain on the N-terminal of annexin consisting of 13 amino acid sequence. Radiolabeled annexin V is used for imaging apoptosis. With an aim to synthesize a probe that can detect cell death akin to annexin V but smaller in size, annexin-13 fragments were derivatized to contain cysteine, cysteine-cysteine and histidine in their sequence at N terminal and were labeled with (99m)Tc via nitrido and carbonyl precursors. The (99m)Tc-labeled annexin-13 derivatives were characterized by HPLC and studied for their stability. In vitro and in vivo studies were carried out in apoptotic HL-60 cells and fibrosarcoma tumor-bearing Swiss mice, respectively. The (99m)Tc complexes were formed in high yields and were found to be stable. HPLC pattern of (99m)Tc nitrido complex of cysteine-cysteine-annexine 13 (CC-Anx13) and (99m)Tc carbonyl complex of histdine-annexin 13 (H-Anx13) revealed the formation of single species. In vitro cell uptake studies with (99m)Tc nitrido complex of cysteine-cysteine-annexin 13 fragment showed 6.5% uptake in apoptotic HL-60 cells. The uptake was found to be specific on testing with apoptotic HL-60 cells. Biodistribution studies of (99m)Tc nitrido complex with CC-Anx13 in fibrosarcoma tumor-bearing Swiss mice revealed optimum tumor uptake of 0.52 (0.17) %ID/g at 1 h pi. (99m)Tc(N)-CC-anx13 showed specific uptake in apoptotic tumor cells and warrants further evaluation.

Evaluation of novel cationic 99mTc-nitrido complexes as radiopharmaceuticals for heart imaging: improving liver clearance with crown ether groups

This report describes the evaluation of a series of novel cationic (99m)Tc-nitrido complexes, [(99m)TcN(DTC)(PNP)]+ (DTC = crown ether-containing dithiocarbamates; PNP = bisphosphine), as potential radiotracers for myocardial perfusion imaging. Synthesis of cationic (99m)Tc-nitrido complexes was accomplished in two steps according to literature methods. Biodistribution studies were performed in rats. Planar images of Sprague-Dawley rats administered with 15+/-2 MBq of cationic (99m)Tc radiotracer were obtained using a PhoGama large field-of-view Anger camera. Samples from both urine and feces were analyzed by a reversed-phase radio-HPLC method. Results from biodistribution studies showed that most of the cationic (99m)Tc-nitrido complexes have a high initial heart uptake with a long myocardial retention. They also show a rapid clearance from the liver and lungs. Cationic complexes [(99m)TcN(L2)(L6)]+ and [(99m)TcN(L4)(L6)]+ show heart/liver ratios four to five times better than that of (99m)Tc-sestamibi due to their much faster liver clearance. Their heart uptake and heart/liver ratio are comparable to that of (99m)TcN-DBODC5 within the experimental error. These findings have been confirmed by the results from imaging studies. Radio-HPLC analysis of urine and feces samples indicated that there was very little metabolism of cationic (99m)Tc-nitrido complexes in rats under anesthesia. The key finding of this study is that lipophilicity remains the most important factor affecting both heart uptake and target-to-background (T/B) ratios. Crown ethers are very useful functional groups to improve the liver clearance of cationic (99m)Tc-nitrido complexes. It is the combination of the appropriate DTCs and bisphosphines that results in cationic (99m)Tc-nitrido complexes with high heart uptake and fast clearance from the liver at the same time. The fast liver clearance of [(99m)TcN(L2)(L6)]+ and [(99m)TcN(L4)(L6)]+ suggests that they might be used to obtain clinically useful images as early as 30 min postinjection. [(99m)TcN(L2)(L6)]+ and [(99m)TcN(L4)(L6)]+ are very promising candidates for further evaluation in more extensive preclinical animal models.

99mTc-labeling of colchicine using [ 99mTc(CO) 3(H 2O) 3] + and [ 99mTc [tbnd]N] 2+ core for the preparation of potential tumor-targeting agents

Multidrug resistance (MDR) mediated by over-expression of P-glycoprotein (Pgp) is one of the major causes of failure of chemotherapy in cancer treatment. Colchicine, a naturally occurring alkaloid, is a Pgp substrate and acts as an antimitotic agent by binding to microtubules. Hence, Colchicine and its analogues radiolabeled with 99mTc may have potential for visualization of MDR in tumors. Here we report 99mTc-labeling of colchicine derivatives using [ 99mTc(CO) 3(H 2O) 3] + and [ 99mTc N] 2+ cores. Trimethylcolchicinic acid synthesized from colchicine was used as the precursor to prepare iminodiacetic acid and dithiocarbamate derivatives which were then radiolabeled with [ 99mTc(CO) 3(H 2O) 3] + and [ 99mTc N] 2+ cores, respectively. Radiolabeling yield for both the complexes was >98% as observed by HPLC and TLC patterns. In vitro studies in tumor cell lines showed significant uptake for 99mTc-carbonyl as well as for 99mTc-nitrido colchicine complexes. Biodistribution studies in Swiss mice bearing fibrosarcoma tumor showed 4.1 ± 1.2% ID/g of uptake at 30 min pi for 99mTc(CO) 3-complex as against 0.42 ± 0.24% ID/g for the 99mTcN-complex. 99mTc(CO) 3–colchicine complex exhibited better pharmacokinetics with lower liver accumulation as compared to the 99mTcN-complex. Thus, colchicine radiolabeled with [ 99mTc(CO) 3(H 2O) 3] + core is more promising with respect to in vivo distribution characteristics in tumor model.

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 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.

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, characterization and biodistribution of new 99mTc nitrido complexes with derivatives of alkyl xanthates

Synthesis, characterization and biodistribution of new 99mTc nitrido complexes with derivatives of alkyl xanthates

Synthesis, characterization and biodistribution of new 99mTc nitrido complexes with derivatives of alkyl xanthates

Synthesis, characterization and biodistribution of new 99mTc nitrido complexes with derivatives of alkyl xanthates

Influence of a 99mTcN core on the biological and physicochemical behavior of 99mTc complexes of L,L-EC and L,L-ECD

99mTc-nitrido complexes of L,L-ethylene dicysteine ( 99mTcN- L,L-EC) and 99mTcN- L,L-ethylene dicysteine diethylester ( 99mTcN- L,L-ECD) were prepared and their characteristics compared to those of the respective 99mTc-oxo complexes. 99mTcN- L,L-EC and 99mTcO- L,L-EC migrate to similar extents during electrophoresis at pH 12, but, at pH 6, 99mTcN- L,L-EC migrates further than 99mTcO- L,L-EC. Renal excretion of 99mTcN- L,L-EC is inferior to that of 99mTcO- L,L-EC, indicating that the TcN-glycine sequence has lower affinity for the renal tubular system. Both 99mTcO- L,L-ECD and 99mTcN- L,L-ECD are neutral, but 99mTcN- L,L-ECD is hydrophilic and shows minimal brain uptake in both mice and the baboon.

Preparation and biological behaviour of 99mTc-carbonyl and 99mTc-nitrido complexes of cysteine and some cysteine esters

The preparation of 99mTcO-, 99mTcN- and 99mTc(CO)-complexes of cysteamine (CYA), cysteine (CYS) and the methyl (CME) and ethyl (CEE) esters of cysteine is described. All complexes were stable and their biological behaviour in mice was studied. Most complexes were found to clear predominantly via the renal pathway with TcN- and Tc(CO)-complexes exhibiting greater urinary clearance than the corresponding TcO-complex. 99mTcN-CME, 99mTc(CO)-CME and 99mTc(CO)-CYS were found to be rapidly cleared via the kidneys and the effect of probenicid on renal clearance was studied to determine whether tubular excretion was involved. The results suggest that tubular secretion is involved in the renal clearance of 99mTcN-CME and Tc(CO)-CYS.

Synthesis, characterization and biodistribution of new 99mTc oxo and nitrido complexes with Bi- and tetradendate unsaturated NS and N 2S 2 Schiff bases derived from 2-aminocyclopentene-1-dithiocarboxylic acid as potential heart imaging agents

The synthesis, characterization and 99mTc labelling of unsaturated diamino dithiol ligands with methyl dithiocarboxylate functions: 2-aminocyclopentene-1-dithiocarboxylic methyl ester (H 2L1), N,N′-ethylene bis (methyl 2-aminocyclopentene-1-dithiocarboxylate) (H 2L 2) and N,N′-propylene bis (methyl 2-aminocyclopentene-1-dithiocarboxylate) (H 2L3) are described. Cationic oxo (TcO) and neutral nitrido (TcN) complexes were obtained. Biodistribution studies in rat showed a good heart uptake of 99mTcN-L2 (2% ID at 5 min) with a high heart-to-blood ratio (5.8 at 5 min), but this complex also exhibited high lung and liver uptake.

Synthesis, characterization and biodistribution of new 99mTc Oxo and nitrido complexes of unsaturated tetradentate (N 2S 2) ligands

Three unsaturated Schiff base tetradentate (N 2S 2 or N 2SO) ligands were synthesized and characterized. Oxo and nitrido 99m-technetium complexes were obtained with these ligands. The nitrido complexes were formed using a new easy method available as a kit. When injected into rats and mice, these lipophilic complexes were able to cross the blood-brain barrier but brain perfusion imaging could not be performed due to the insufficient uptake and retention time.