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A novel ternary ligand system useful for preparation of cationic (99m)Tc-diazenido complexes and (99m)Tc-labeling of small biomolecules.

ABSTRACT: This report describes a novel ternary ligand system composed of a phenylhydrazine, a crown ether-containing dithiocarbamate (DTC), and a PNP-type bisphosphine (PNP). The combination of three different ligands with (99m)Tc results in cationic (99m)Tc-diazenido complexes, [(99m)Tc(NNAr)(DTC)(PNP)]+, with potential radiopharmaceuticals for heart imaging. Synthesis of cationic (99m)Tc-diazenido complexes can be accomplished in two steps. For example, the reaction of phenylhydrazine with (99m)TcO4- at 100 degrees C in the presence of excess stannous chloride and 1,2-diaminopropane-N,N,N',N'-tetraacetic acid (PDTA) results in the [(99m)Tc(NNPh)(PDTA)n] intermediate, which then reacts with sodium N-(dithiocarbamato)-2-aminomethyl-15-Crown-5 (L4) and N,N-bis[2-(bis(3-ethoxypropyl)phosphino)ethyl]ethoxyethylamine (PNP6) at 100 degrees C for 15 min to give the complex, [(99m)Tc(NNPh)(L4)(PNP6)]+ in high yield (>90%). Cationic complexes [(99m)Tc(NNPh)(DTC)(PNP)]+ are stable for > or = 6 h. Their composition was determined to be 1:1:1:1 for Tc:NNPh:DTC:PNP using the mixed-ligand experiments on the tracer ((99m)Tc) level and was further confirmed by the ESI-MS spectral data of a model compound [Re(NNPh)(L4)(L6)]+. It was found that both DTCs and bisphosphines have a significant impact on the lipophilicity of their cationic (99m)Tc-diazenido complexes. Results from a (99m)Tc-labeling efficiency experiment showed that 4-hydrazinobenzoic acid (HYBA) might be useful as a bifunctional coupling agent for (99m)Tc-labeling of small biomolecules. However, the (99m)Tc-labeling efficiency of HYBA is much lower than that of 6-hydrazinonicotinic acid (HYNIC) with tricine and trisodium triphenylphosphine-3,3',3''-trisulfonate (TPPTS) as coligands.

SUBMITTER: Kim YS

PROVIDER: S-EPMC2597566 | biostudies-literature | 2006 Mar-Apr

REPOSITORIES: biostudies-literature

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A novel ternary ligand system useful for preparation of cationic (99m)Tc-diazenido complexes and (99m)Tc-labeling of small biomolecules.

Kim Young-Seung YS He Zhengjie Z Hsieh Wen-Yuan WY Liu Shuang S

Bioconjugate chemistry 20060301 2

This report describes a novel ternary ligand system composed of a phenylhydrazine, a crown ether-containing dithiocarbamate (DTC), and a PNP-type bisphosphine (PNP). The combination of three different ligands with (99m)Tc results in cationic (99m)Tc-diazenido complexes, [(99m)Tc(NNAr)(DTC)(PNP)]+, with potential radiopharmaceuticals for heart imaging. Synthesis of cationic (99m)Tc-diazenido complexes can be accomplished in two steps. For example, the reaction of phenylhydrazine with (99m)TcO4- a ...[more]

PMID: 16536480

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Project description:This study sought to evaluate K(HYNIC)(2) (K = lysine and HYNIC = 6-hydrazinonicotinyl) as a bifunctional chelator for (99m)Tc-labeling of biomolecule. In this study, four K(HYNIC)(2)-conjugated cyclic RGD peptides, K(HYNIC)(2)-RGD(2) (RGD(2) = E[c(RGDfK)](2)), K(HYNIC)(2)-3G-RGD(2) (3G-RGD(2) = Gly-Gly-Gly-E[Gly-Gly-Gly-c(RGDfK)](2)), K(HYNIC)(2)-2P-RGD(2) (2P-RGD(2) = E[PEG4-c(RGDfK)](2), and PEG(4) = 15-amino-4,7,10,13-tetraoxapentadecanoic acid), and K(HYNIC)(2)-3P-RGD(2) (3P-RGD(2) = PEG4-E[PEG4-c(RGDfK)]2) were prepared, and evaluated for their integrin αvβ3 binding affinity. IC(50) values were determined to be 47 ± 2, 35 ± 2, 37 ± 2, 85 ± 2, and 422 ± 15 nM for K(HYNIC)(2)-2P-RGD(2), K(HYNIC)(2)-3P-RGD(2), K(HYNIC)(2)-3G-RGD(2), K(HYNIC)(2)-RGD(2), and c(RGDyK), respectively, against (125)I-echistatin bound to U87MG cells. Macrocyclic complexes [(99m)Tc(K(HYNIC)(2)-RGD(2))(tricine)] (1), [(99m)Tc(K(HYNIC)(2)-3G-RGD(2))(tricine)] (2), [(99m)Tc(K(HYNIC)(2)-2P-RGD(2))(tricine)] (3), and [(99m)Tc(K(HYNIC)(2)-3P-RGD(2))(tricine)] (4) were prepared, and evaluated in athymic nude mice bearing U87MG glioma xenografts for their tumor targeting capability and biodistribution. It was found that 1-4 all had high solution stability and more than two isomers, as evidenced by the presence of multiple radiometric peaks in their radio-HPLC chromatograms. The tumor uptake of 1-4 was 3.78 ± 0.81, 7.46 ± 1.68, 9.74 ± 1.65, and 8.59 ± 1.52%ID/g, respectively, which was completely consistent with trend of integrin α(v)β(3) binding affinity for cyclic RGD peptides. Replacing [(99m)Tc(HYNIC)(tricine)(TPPTS)] (TPPTS = trisodium triphenylphosphine-3,3',3"-trisulfonate) with [(99m)Tc(K(HYNIC)(2))(tricine)] had little impact on radiotracer tumor uptake; but it had significant effect on the uptake of radiotracer in kidneys, lungs, and spleen. The tumor was clearly visualized by SPECT/CT with excellent contrast in a glioma-bearing mouse administered with 4. K(HYNIC)(2) would be particularly useful for (99m)Tc-labeling of small biomolecules with one or more disulfide linkages.

Project description:This study sought to evaluate [(99m)Tc(HYNIC-Galacto-RGD2)(tricine)(TPPTS)] ((99m)Tc-Galacto-RGD2: HYNIC = 6-hydrazinonicotinyl; Galacto-RGD2 = Glu[cyclo[Arg-Gly-Asp-D-Phe-Lys(SAA-PEG2-(1,2,3-triazole)-1-yl-4-methylamide)]]2 (SAA = 7-amino-L-glycero-L-galacto-2,6-anhydro-7-deoxyheptanamide, and PEG2 = 3,6-dioxaoctanoic acid); and TPPTS = trisodium triphenylphosphine-3,3',3?-trisulfonate) as a new radiotracer for tumor imaging. Galacto-RGD2 was prepared via the copper(I)-catalyzed 1,3-dipolar azide-alkyne Huisgen cycloaddition. HYNIC-Galacto-RGD2 was prepared by reacting Galacto-RGD2 with sodium succinimidyl 6-(2-(2-sulfonatobenzaldehyde)hydrazono)nicotinate (HYNIC-OSu) in the presence of diisopropylethylamine, and was evaluated for its integrin ?v?3 binding affinity against (125)I-echistatin bound to U87MG glioma cells. The IC50 value for HYNIC-Galacto-RGD2 was determined to be 20 ± 2 nM. (99m)Tc-Galacto-RGD2 was prepared in high specific activity (? 185 GBq/?mol) and high radiochemical purity (>95%), and was evaluated in athymic nude mice bearing U87MG glioma xenografts for its tumor-targeting capability and biodistribution. The tumor uptake of (99m)Tc-Galacto-RGD2 was 10.30 ± 1.67, 8.37 ± 2.13, 6.86 ± 1.33, and 5.61 ± 1.52%ID/g at 5, 30, 60, and 120 min p.i., respectively, which was in agreement with high integrin ?v?3 expression on glioma cells and neovasculature. Its lower uptake in intestines, lungs, and spleen suggests that (99m)Tc-Galacto-RGD2 has advantages over (99m)Tc-3P-RGD2 ([(99m)Tc(HYNIC-3P-RGD2)(tricine)(TPPTS)]: 3P-RGD2 = PEG4-E[PEG4-c(RGDfK)]2; PEG4 = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) for imaging tumors in the chest and abdominal regions. U87MG tumors were readily detected by SPECT and the tumor uptake of (99m)Tc-Galacto-RGD2 was integrin ?v?3-specific. (99m)Tc-Galacto-RGD2 also had very high metabolic stability. On the basis of results from this study, it was concluded that (99m)Tc-Galacto-RGD2 is an excellent radiotracer for imaging integrin ?v?3-positive tumors and related metastases.

Project description:PurposeSentinel lymph node (SLN) biopsy has proven to reliably stage the clinically negative neck in early-stage oral squamous cell carcinoma (OSCC). [99mTc]Tc-tilmanocept may be of benefit in OSCC with complex lymphatic drainage patterns and close spatial relation to SLNs.MethodsA prospective within-patient evaluation study was designed to compare [99mTc]Tc-tilmanocept with [99mTc]Tc-nanocolloid for SLN detection. A total of 20 patients with early-stage OSCC were included, who underwent lymphoscintigraphy with both tracers. Both lymphoscintigraphic images of each patient were evaluated for SLN detection and radiotracer distribution at 2-4 h post-injection.ResultsThe injection site's remaining radioactivity was significantly lower for [99mTc]Tc-tilmanocept (29.9%), compared with [99mTc]Tc-nanocolloid (60.9%; p < 0.001). Radioactive uptake in SLNs was significantly lower for [99mTc]Tc-tilmanocept (1.95%) compared with [99mTc]Tc-nanocolloid (3.16%; p = 0.010). No significant difference was seen in SLN to injection site ratio in radioactivity between [99mTc]Tc-tilmanocept (0.066) and [99mTc]Tc-nanocolloid (0.054; p = 0.232). A median of 3.0 and 2.5 SLNs were identified with [99mTc]Tc-tilmanocept and [99mTc]Tc-nanocolloid, respectively (p = 0.297). Radioactive uptake in higher echelon nodes was not significantly different between [99mTc]Tc-tilmanocept (0.57%) and [99mTc]Tc-nanocolloid (0.86%) (p = 0.052). A median of 2.0 and 2.5 higher echelon nodes was identified with [99mTc]Tc-tilmanocept and [99mTc]Tc-nanocolloid, respectively (p = 0.083).Conclusion[99mTc]Tc-tilmanocept had a higher injection site clearance, but at the same time a lower uptake in the SLN, resulting in an SLN to injection site ratio, which was not significantly different from [99mTc]Tc-nanocolloid. The relatively low-radioactive uptake in SLNs of [99mTc]Tc-tilmanocept may limit intraoperative detection of SLNs, but can be overcome by a higher injection dose.

Project description:Introduction(99m)Tc-Teboroxime ([(99m)TcCl(CDO)(CDOH)2BMe]) is a member of the BATO (boronic acid adducts of technetium dioximes) class of (99m)Tc(III) complexes. This study sought to explore the impact of co-ligands on solution stability, heart uptake and myocardial retention of [(99m)Tc(L)(CDO)(CDOH)2BMe] ((99m)Tc-Teboroxime: L=Cl; (99m)Tc-Teboroxime(F): L=F; (99m)Tc-Teboroxime(SCN): L=SCN; and (99m)Tc-Teboroxime(N3): L=N3).MethodsRadiotracers (99m)Tc-Teboroxime(L) (L=F, SCN and N3) were prepared by reacting (99m)Tc-Teboroxime with NaF, NaSCN and NaN3, respectively. Biodistribution and imaging studies were carried out in Sprague-Dawley rats. Image quantification was performed to compare their heart retention and liver clearance kinetics.ResultsComplexes (99m)Tc-Teboroxime(L) (L=F, SCN and N3) were prepared in high yield with high radiochemical purity. All new radiotracers were stable for >6h in the kit matrix. In its HPLC chromatogram, (99m)Tc-Teboroxime showed one peak at ~15.5 min, which was shorter than that of (99m)Tc-Teboroxime(F) (~16.4 min). There were two peaks for (99m)Tc-Teboroxime(SCN) at 16.5 and 18.3 min. (99m)Tc-Teboroxime(N3) appeared as a single peak at 18.4 min. Their heart retention and liver clearance curves were best fitted to the bi-exponential decay function. The half-times of fast/slow components were 1.6±0.4/60.7±8.9 min for (99m)Tc-Teboroxime, 0.8±0.2/101.7±20.7 min for (99m)Tc-Teboroxime(F), 1.2±0.3/84.8±16.6 min for (99m)Tc-Teboroxime(SCN), and 2.9±0.9/51.6±5.0 min for (99m)Tc-Teboroxime(N3). The 2-min heart uptake followed the order of (99m)Tc-Teboroxime (3.00±0.37%ID/g)>(99m)Tc-Teboroxime(N3) (2.66±0.01 %ID/g)≈(99m)Tc-Sestamibi (2.55±0.46 %ID/g)>(99m)TcN-MPO (2.38±0.15 %ID/g). (99m)Tc-Teboroxime remains the best in first-pass extraction. The best image acquisition window is 0-5 min for (99m)Tc-Teboroximine and 0-15 min for (99m)Tc-Teboroximine(N3).ConclusionCo-ligands had significant impact on the heart uptake and myocardial retention of complexes [(99m)Tc(L)(CDO)(CDOH)2BMe] (L=Cl, F, SCN and N3). Future studies should be directed towards minimizing the liver uptake and radioactivity accumulation in the blood vessels while maintaining their high heart uptake.

Project description:BackgroundMolecular breast imaging (MBI) performed with 99mTc sestamibi has been shown to be a valuable technique for the detection of breast cancer. Alternative radiotracers such as 99mTc maraciclatide may offer improved uptake in breast lesions. The purpose of this study was to compare relative performance of 99mTc sestamibi and 99mTc maraciclatide in patients with suspected breast cancer, using a high-resolution dedicated gamma camera for MBI. Women with breast lesions suspicious for malignancy were recruited to undergo two MBI examinations-one with 99mTc sestamibi and one with 99mTc maraciclatide. A radiologist interpreted MBI studies in a randomized, blinded fashion to assign an assessment score (1-5) and measured lesion size. Lesion-to-background (L/B) ratio was measured with region-of-interest analysis.ResultsAmong 39 analyzable patients, 21 malignant tumors were identified in 21 patients. Eighteen of 21 tumors (86%) were seen on 99mTc sestamibi MBI and 19 of 21 (90%) were seen on 99mTc maraciclatide MBI (p = 1). Tumor extent measured with both radiopharmaceuticals correlated strongly with pathologic size (99mTc sestamibi, r = 0.84; 99mTc maraciclatide, r = 0.81). The L/B ratio in detected breast cancers was similar for the two radiopharmaceuticals: 1.55 ± 0.36 (mean ± S.D.) for 99mTc sestamibi and 1.62 ± 0.37 (mean ± S.D.) for 99mTc maraciclatide (p = 0.53). No correlation was found between the L/B ratio and molecular subtype for 99mTc sestamibi (r s = 0.12, p = 0.63) or 99mTc maraciclatide (r s = -0.12, p = 0.64). Of 20 benign lesions, 10 (50%) were seen on 99mTc sestamibi and 9 of 20 (45%) were seen on 99mTc maraciclatide images (p = 0.1). The average L/B ratio for benign lesions was 1.34 ±0.40 (mean ±S.D.) for 99mTc sestamibi and 1.41 ±0.52 (mean ±S.D.) for 99mTc maraciclatide (p = 0.75). Overall diagnostic performance was similar for both radiopharmaceuticals. AUC from ROC analysis was 0.83 for 99mTc sestamibi and 0.87 for 99mTc maraciclatide (p = 0.64).Conclusions99mTc maraciclatide offered comparable lesion uptake to 99mTc sestamibi, in both malignant and benign lesions. There was good correlation between lesion extent and uptake measured from both radiopharmaceuticals. 99mTc maraciclatide offered a marginal (but not significant) improvement in sensitivity over 99mTc sestamibi. Our findings did not support an association between the uptake of either radiopharmaceutical and tumor molecular subtype.Trial registrationClinicalTrials.gov, NCT00888589.

Dataset Information

A novel ternary ligand system useful for preparation of cationic (99m)Tc-diazenido complexes and (99m)Tc-labeling of small biomolecules.

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A novel ternary ligand system useful for preparation of cationic (99m)Tc-diazenido complexes and (99m)Tc-labeling of small biomolecules.

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