Mithu Chanda

Synthesis of 99mTc-EC-AMT as an imaging probe for amino acid transporter systems in breast cancer

ObjectiveThis study was to develop a 99mTc-labeled α-methyl tyrosine (AMT) using L,L-ethylenedicysteine (EC) as a chelator and to evaluate its potential in breast tumor imaging in rodents. MethodsEC-AMT was synthesized by reacting EC and 3-bromopropyl AMT (N-BOC, ethyl ester) in ethanol/potassium carbonate solution. EC-AMT was labeled with 99mTc in the presence of tin (II) chloride. Rhenium-EC-AMT (Re-EC-AMT) was synthesized as a reference standard for 99mTc-EC-AMT. To assess the cellular uptake kinetics of 99mTc-EC-AMT, 13 762 rat breast cancer cells were incubated with 99mTc-EC-AMT for 0–2 h. To investigate the transport mechanism, the same cell line was used to conduct the competitive inhibition study using L-tyrosine. Tissue distribution of 99mTc-EC-AMT was determined in normal rats at 0.5–4 h. Planar imaging of breast tumor-bearing rats was performed at 30 and 90 min. The data were compared with those of 18F-2-fluoro-2-deoxy-glucose. Blocking uptake study using unlabeled AMT was conducted to investigate the transport mechanism of 99mTc-EC-AMT in vivo. ResultsStructures of EC-AMT and Re-EC-AMT were confirmed by nuclear magnetic resonance, high performance liquid chromatography and mass spectra. In-vitro cellular uptake of 99mTc-EC-AMT in 13 762 cells was increased as compared with that of 99mTc-EC and could be inhibited by L-tyrosine. Biodistribution in normal rats showed high in-vivo stability of 99mTc-EC-AMT. Planar scintigraphy at 30 and 90 min showed that 99mTc-EC-AMT could clearly visualize tumors. 99mTc-EC-AMT uptake could be significantly blocked by unlabeled AMT in vivo. ConclusionThe results indicate that 99mTc-EC-AMT, a new amino acid transporter-based radiotracer, is suitable for breast tumor imaging.

Synthesis and Evaluation of Amino Acid-Based Radiotracer 99mTc-N4-AMT for Breast Cancer Imaging

Purpose. This study was to develop an efficient synthesis of 99mTc-O-[3-(1,4,8,11-tetraazabicyclohexadecane)-propyl]-α-methyl tyrosine (99mTc-N4-AMT) and evaluate its potential in cancer imaging. Methods. N4-AMT was synthesized by reacting N4-oxalate and 3-bromopropyl AMT (N-BOC, ethyl ester). In vitro cellular uptake kinetics of 99mTc-N4-AMT was assessed in rat mammary tumor cells. Tissue distribution of the radiotracer was determined in normal rats at 0.5–4 h, while planar imaging was performed in mammary tumor-bearing rats at 30–120 min. Results. The total synthesis yield of N4-AMT was 14%. Cellular uptake of 99mTc-N4-AMT was significantly higher than that of 99mTc-N4. Planar imaging revealed that 99mTc-N4-AMT rendered greater tumor/muscle ratios than 99mTc-N4. Conclusions. N4-AMT could be synthesized with a considerably high yield. Our in vitro and in vivo data suggest that 99mTc-N4-AMT, a novel amino acid-based radiotracer, efficiently enters breast cancer cells, effectively distinguishes mammary tumors from normal tissues, and thus holds the promise for breast cancer imaging.

Technologies for translational imaging using generators in oncology

Improvement of scintigraphic tumor imaging is extensively determined by the development of more tumor specific radiopharmaceuticals. Thus, to improve the differential diagnosis, prognosis, planning and monitoring of cancer treatment, several functional pharmaceuticals have been developed. The application of molecular targets for cancer imaging, therapy and prevention using generator-produced isotopes is the major focus of many ongoing research projects. Radionuclide imaging modalities (single photon emission computed tomography, SPECT; positron emission tomography, PET) are diagnostic cross-sectional imaging techniques that map the location and concentration of radionuclide-labeled radiotracers. Generator produced isotopes, such as 99mTc and 68Ga, are readily available and affordable. 99mTc (t1/2=6 hr; 140 keV) is used for SPECT and 68Ga (t1/2=68 min; 511 keV, 89%) is used for PET. 99mTc- and 68Ga-labeled agents using various chelators have been synthesized and their potential uses to assess tumor targets have been evaluated. Molecular targets labeled with 99mTc and 68Ga can be utilized for the prediction of therapeutic response, monitoring tumor response to treatment and aiding in the differential diagnosis of tumor versus non-tumor tissue. Molecular targets for oncological research in (1) cell apoptosis, (2) gene and nucleic acid-based approach, (3) angiogenesis (4) tumor hypoxia, and (5) metabolic imaging are discussed. Numerous imaging ligands in these categories have been developed and evaluated in animals and humans. Molecular targets were imaged and their potential to redirect optimal cancer diagnosis and therapeutics was demonstrated.

99mTc-N4amG: Synthesis Biodistribution and Imaging in Breast Tumor-bearing Rodents

(99m)Tc-N4-guanine ((99m)Tc-N4amG) was synthesized and evaluated in this study. Cellular uptake and cellular fraction studies were performed to evaluate the cell penetrating ability. Biodistribution and planar imaging were conducted in breast tumor-bearing rats. Up to 17%ID uptake was observed in cellular uptake study with 40% of (99m)Tc-N4amG was accumulated in the nucleus. Biodistribution and scintigraphic imaging studies showed increased tumor/muscle count density ratios as a function of time. Our results demonstrate the feasibility of using (99m)Tc-N4amG in tumor specific imaging.