The synthesis of a new macromolecule for the sentinel node detection: 99mTc-gly-mannosyl-dextran.

OBJECTIVE: We aimed to design and synthesize a new macromolecule for sentinel node detection to improve the imaging quality and avoid possible adverse effect. BACKGROUND: The imaging of sentinel lymph node has been an important field in the nuclear medicine. A lot of imaging agents have been developed, including Tc-sulfer colloid, Tc-labeled dextrans and the latest Tc-DTPA-mannosyl-dextran. With the technology advanced, the imaging ability of the agents has been better and better. However, there are still some drawbacks. MATERIALS AND METHODS: The new macromolecule agent was based on the dextran macromolecule backbone. Then the gly-gly-gly and mannose molecules were conjugated onto the backbone proportionally by targeting two different reaction sites. Once the new macromolecule was labelled with Tc, its imaging ability was tested by single-photon emission computed tomography scanning with Tc-sulfur colloid as the comparison. RESULTS: The average numbers of gly-gyl-gyl and mannosyl groups on the dextran backbone are determined to be ∼1: 2 per dextran. The average molecular diameter and molecular weight are measured to be 5.4±0.7 nm and 10 324 g/mol, respectively. The macromolecule is labelled by Tc with 93.2±2.4% radiochemical yield. The lymphatic imaging by single-photon emission computed tomography with the labeled compound showed no worse imaging ability but cost less time than the commercially available Tc-sulfur colloid. CONCLUSION: A new macromolecule imaging agent for sentinel node detection has been synthesized with better imaging ability and less imaging time cost.

Synthesis and evaluation of Tc-99m DTPA-glutathione as a non-invasive tumor imaging agent in a mouse colon cancer model.

PURPOSE: Glutathione (GSH) plays a critical role in detoxification reactions by reducing the levels of reactive oxygen species in cancer cells. This study aimed to develop technetium (Tc)-99m diethylenetriaminepentaacetic acid (DTPA)-GSH as a tumor imaging agent, and to evaluate the diagnostic performance of Tc-99m DTPA-GSH in terms of its ability to differentiate tumors from inflammatory lesions. METHODS: DTPA-GSH was synthesized by reaction of GSH with DTPA anhydride under anhydrous conditions in a nitrogen atmosphere. DTPA-GSH was then reacted with Tc-99m sodium pertechnetate in a tin (II) chloride (SnCl2) solution. Gamma camera imaging was performed after intravenous injection of Tc-99m DTPA-GSH into a mouse CT-26 colon cancer model, or a mouse model of inflammation induced by the intramuscular injection of Freund's complete adjuvant. RESULTS: DTPA-GSH was successfully prepared via a straightforward synthetic procedure and radiolabeled with Tc-99m at a high labeling efficiency (>95%). Tc-99m DTPA-GSH was strongly internalized by tumors in colon cancer model mice, with the tumor-to-normal muscle ratio of the complex reaching 4.3±0.9 at 4 h. By contrast, Tc-99m DTPA-GSH showed relatively weak uptake in inflammatory lesions (target-to-non-target ratio=2.0±0.3 at 4 h). A competition study showed that the uptake of Tc-99m DTPA-GSH into tumors was blocked by co-injection with high concentrations of free GSH. CONCLUSIONS: The results of this work indicate that Tc-99m DTPA-GSH is a good candidate for development as a non-invasive tumor imaging agent. Furthermore, Tc-99m DTPA-GSH effectively distinguished between cancerous tissue and inflammatory lesions.

Synthesis of [DTPA-bis(D-ser)] chelate (DBDSC): an approach for the design of SPECT radiopharmaceuticals based on technetium.

D-Serine is a physiological coagonist of the N-methyl D-aspartate (NMDA) type of glutamate receptor-a key excitatory neurotransmitter receptor in the brain. D-Serine appears to be a part of the synapse through a variety of transporters located on both neurons and astrocytes. The development of 99mTc radiolabeled amino acid based radiopharmaceuticals for imaging a variety of tumors has found to be useful in diagnostic imaging. Diethylene triamine penta acetic acid (DTPA) is one of the most well-known chelating reagent for the production of stable complexes with various heavy metal ions. We have synthesized [DTPA-bis(D-ser)] in 90% yield and analyzed the chelate by spectroscopic techniques. The DBDSC chelate binds to 99mTc with high efficiency at ambient temperature. The resulting chelate is stable under physiological conditions (37oC, pH=7.4) for at least 24 h after radiocomplexation. The receptor binding studies of 99mTc-[DTPA-bis(D-ser)] in established lung adeno carcinoma A549 exhibited Kd value to be 26nM. A549 Tumor in athymic mice was accumulated in the γ-images. The major accumulation of the radiotracer was observed in tumor, followed by kidneys. 99mTc-[DTPA-bis(D-ser)] has promising utility as SPECT-radiopharmaceutical.

Sulfonylurea receptor as a target for molecular imaging of pancreas beta cells with (99m)Tc-DTPA-glipizide.

OBJECTIVE: This study was aimed to assess pancreas beta cell activity using (99m)Tc-diethyleneaminepentaacetic acid-glipizide (DTPA-GLP), a sulfonylurea receptor agent. The effect of DTPA-GLP on the blood glucose level in rats was also evaluated. METHODS: DTPA dianhydride was conjugated with GLP in the presence of sodium amide, yielding 60%. Biodistribution and planar images were obtained at 30-120 min after injection of (99m)Tc-DTPA-GLP (1 mg/rat, 0.74 and 11.1 MBq per rat, respectively) in normal female Fischer 344 rats. The control group was given (99m)Tc-DTPA. To demonstrate pancreas beta cell uptake of (99m)Tc-DTPA-GLP via a receptor-mediated process, a group of rats was pretreated with streptozotocin (a beta cell toxin, 55 mg/kg, i.v.) and the images were acquired at immediately-65 min on day 5 post-treatment. The effect on the glucose levels after a single administration (ip) of DTPA-GLP was compared to glipizide (GLP) for up to 6 h. RESULTS: The structure of DTPA-GLP was confirmed by NMR, mass spectrometry and HPLC. Radiochemical purity assessed by ITLC was >96%. (99m)Tc-DTPA-GLP showed increased pancreas-to-muscle ratios, whereas (99m)Tc-DTPA showed decreased ratios at various time points. Pancreas could be visualized with (99m)Tc-DTPA-GLP in normal rat, however, (99m)Tc-DTPA has poor uptake suggesting the specificity of (99m)Tc-DTPA-GLP. Pancreas beta cell uptake could be blocked by pre-treatment with streptozotocin. DTPA-GLP showed an equal or better response in lowering the glucose levels compared to the existing GLP drug. CONCLUSIONS: It is feasible to use (99m)Tc-DTPA-GLP to assess pancreas beta cell receptor recognition. (99m)Tc-DTPA-GLP may be helpful in evaluating patients with diabetes, pancreatitis and pancreatic tumors.

Technetium-99m DTPA dimethyl ester: a renal function imaging agent. Comparative studies in animals with technetium-99m mercaptoacetyl triglycine and 131I-ortho-iodohippurate.

The dimethyl ester of diethylene triamine penta-acetic acid (DMDTPA) (I) can be easily and efficiently labelled with 99mTc. This method can be readily adapted for kit formulations to produce a highly stable and very pure chelate, as shown by paper electrophoresis and reverse-phase high performance liquid chromatography experiments. In mice, this chelate was excreted unchanged in the urine, and the amount of renal excretion was much higher than that of 99mTc-DTPA and comparable with that of 99mTc-mercaptoacetyl triglycine (99mTc-MAG(3)) at two different time points. The renal excretion of co-injected 131I-ortho-iodohippurate (131I-OIH), however, was significantly greater than that of the 99mTc chelates. The renal clearance values of 99mTc-DMDTPA and 99mTc-MAG(3) were also similar and exceeded the corresponding value for 99mTc-DTPA, but were only half that of the 131I-OIH value in the rat. The renograms for 99mTc-DMDTPA and 99mTc-MAG(3) showed overall similarity in a dog model. The diethyl ester (III) and monoethyl ester (II) of DTPA, after labelling with 99mTc, produced the same chelate, as shown by analytical results and biological data, indicating that one of the ester groups in the DTPA diester is dealkylated during the chelation procedure. To confirm this, two more ligands, diethylene triamine 1,4,7,7-tetra-acetic acid (IV) and diethylene triamine 1,4,7-triacetic acid (V), were synthesized, resembling DTPA monoalkyl ester (II) and dialkyl ester (I, III), respectively, in the arrangement of the donor atoms. Ligand IV but not ligand V, on 99mTc chelation, can generate the specific pharmacophore for renal tubular transport that is also present in the ester chelates 99mTc-I, 99mTc-II and 99mTc-III, as shown by their decreased renal excretion in mice pretreated with a renal tubular transport inhibitor such as probenecid.

Sentinel node imaging via a nonparticulate receptor-binding radiotracer.

UNLABELLED: Technetium-99m-labeled polydiethylenetriamine pentaacetic acid polymannosyl polylysine (DTPA-man-PL) was synthesized and tested for lymph node scintigraphy by subcutaneous administration. The agent was designed for receptor-mediated uptake by mannosebinding protein, which resides on the plasma membrane of reticuloendothelial cells. METHODS: Subcutaneous injections of a 99mTc-labeled agent having 18 DTPA and 82 mannosyl groups attached to a polylysine of 100 units ([99mTc]DTPA18-man82-PL100) were made at the level of the metacarpus and metatarsus of three healthy rabbits. Images were acquired at 1, 6, 12 and 24 hr. Popliteal and axillary nodes were then assayed for percent of injected dose (%ID). A negative control study was performed in three normal rabbits with [99mTc]DTPA18-PL100. RESULTS: Significant differences in mean 24-hr %ID between the receptor specific and nonspecific agents were observed for both the popliteal (p < 0.006) and axillary (p < 0.012) nodes. Popliteal percent injected dose at 24 hr was 3.00 +/- 0.72% for [99mTc]DTPA-man-PL and 0.13 +/- 0.08% for [99mTc] DTPA-polylysine. Axillary accumulation at 24 hr was 2.84 +/- 0.83% for [99mTc]DTPA-mannosyl-polylysine and 0.22 +/- 0.12% for [99mTc] DTPA-polylysine. Percent injected dose of the receptor-specific agent was highest (4%) during the 6-hr scan. Accumulation of the nonspecific agent by the popliteal and axillary nodes at 6-hr postinjection was approximately 0.5%. CONCLUSION: This study provides proof of principle for lymphoscintigraphy by receptor-mediated delivery of a nonparticulate imaging agent.