Li-Ren Kuang

Synthesis of [18F]Fluoroalanine and [18F]Fluorotamoxifen for Imaging Breast Tumors

To develop ligands for imaging breast tumors, [18F]fluoro analogue of tamoxifen and [18F]fluoroalanine were radiosynthesized. In vivo biodistribution studies were performed in mammary tumor-bearing rats. In studies on the biodistribution of an [18F]fluoro analogue of tamoxifen, tumor uptake decreased when rats were pretreated with diethylstilbestrol (DES), suggesting that tracer uptake in tumors was receptor-mediated. An estrogen receptor assay indicated that tumors have a receptor density of 7.5 fmol/mg protein. Studies of the distribution of [18F]fluoroalanine in tissue showed that the tumor-to-tissue ratio increases as a function of time. Positron emission tomography (PET) images of tumor-bearing rats demonstrated that tumors can be visualized 1 h after rats are injected with an [18F]fluoro analogue of tamoxifen. PET imaging of pigs after injection of 10 mCi of [18F]fluoro analogue of tamoxifen showed uterine uptake that could be blocked by DES (50 mg). The findings suggest that both radiotracers are useful for imaging breast tumors.

Biodistribution of Cyclic Carbonate of Ioxilan: A Radiopaque Particulate Macrophage Imaging Agent

RATIONALE AND OBJECTIVES A biodegradable radiopaque particulate contrast agent formulated from cyclic carbonate of ioxilan (IXC), which is a prodrug of nonionic water-solubel contrast ioxilan, recently has been developed. This contrast agent enhances liver attenuation and is cleared from the body as ioxilan. In the current study, we tested whether the biodistribution of IXC particles would be affected by the characteristics of particles. METHODS IXC nanoparticles (average diameter = 290 nm) and IXC microparticles (average diameter = 1.7 mm) were prepared, characterized, and injected intravenously (i.v.; 50 mg I/kg body weight) into rats. Two sensitive, reproducible analytic methods--inductively coupled plasma-mass spectrometry (ICP-MS) and high-performance liquid chromatography (HPLC)- were used to quantify tissue iodine and ioxilan concentrations. RESULTS Both IXC nanoparticles and microparticles were taken up in the liver and spleen. The IXC nanoparticles remained in the liver at high concentrations for 6 hr and were slowly cleared. They also gave a high blood iodine concentration in the first 5 min after i.v. injection, suggesting their potential use as a blood-pool imaging agent. Unlike the nanoparticles, the microparticles had a significantly lower uptake by the kidney. CONCLUSION Because of reduced renal uptake, microparticles are a preferred macrophage imaging agent. Biodegradable radiopaque particles may be used either as blood-pool imaging agents or as macrophage imaging agents depending on their size and distribution characteristics. The ICP-MS and HPLC methods are useful for biodistribution studies of iodinated contrast agents.

N,N-Diethylfluoromethyltamoxifen: Synthesis, assignment of 1H and 13C spectra and receptor assay

Abstract (cis) and (trans)N,N-diethylfluoromethyltamoxifen (1-[4-(2-diethylaminoethoxy)phenyl]-1,2-diphenyl-5-fluoro-1-pentene) were synthesized from clomiphene in a three-step procedure and both isomers were differentiated by the concerted application of two-dimensional NMR techniques. In in vitro estrogen receptor assay from pig uterus using [3H]-estradiol (5 nM), the IC50 values were: N,N-diethylfluorotamoxifen cis 5 μM, trans 1 μM; tamoxifen 30 μM. In human MCF7 cell growth assay, the IC50 values were cis 4.5 μM, trans 11.8 μM, tamoxifen 11.0 μM. The data suggest that the fluoro analog of tamoxifen has potential for imaging estrogen receptors by positron emission tomography (PET) and may be used to predict the efficacy of breast tumor therapy.

Radiolabeled Tamoxifen Analogues for Imaging Breast Cancer with Spect

This study is aimed at developing SPECT ligands to image breast tumors. 99mTc-labeled tamoxifen (TX) analogue was prepared by reacting hydroxyethylthio TX analogue with reduced Tc-IV. The yield was 50–60% (purity >99%). 131I-TX was prepared by treating tosyl-TX with Na131I. The yield was 20–25% (>99% purity). Biodistribution studies of both analogues were performed in DMBA-induced mammary tumor-bearing rats (10 μCi/rat, i.v., n=3/timeinterval). Biodistribution 99mTc-TX at 1, 2, 4, 6 and 18 hrs showed a tumor uptake value (% injected dose/gram tissue) of 0.37±0.058, 0.38±0.066, 0.27±0.041, 0.28±0.124 and 0.10±0.013. Tumor/blood ratio ranged from 0.11 to 0.07. Tumor/muscle ratio ranged from 5.68 to 7.38. Biodistribution of 131I-TX at 1, 3, 6 and 24 hrs showed a tumor uptake value 0.18±0.062, 0.23±0.152, 0.26±0.166 and 0.27±0.016. When rats primed with estradiol (60 μg/rat, 3 days, s.c), the value changed to 0.30±0.033, 0.42± to 0.039, 0.48±0.107, and 0.40±0.123. Tumor/blood ratio ranged from 1.95 to 11.0. When rats pretreated with DES (1.2 mg/rat, iv), the tumor uptake value changed to 0.32±0.058 (99mTc-TX, 2 h) and 0.22±0.059 (131I-TX, 6 h). In rats pretreated with estradiol, a significant increase in tumor uptake value was observed after 131I-TX postinjection. 99mTc-TX uptake in tumor could not be blocked by DES, suggesting the uptake was not due to a receptor-mediated process. 131I-TX may be useful in differentiating functioning ER(+) breast tumors.

Evaluation of intratumoral injection of poly(d,l-lactide) cisplatin microspheres in rats with breast tumors using [131I]iodomisonidazole (IMISO)

AbstractThis study utilized [131I]iodomisonidazole (IMISO) to examine changes in tumor hypoxia after therapy of breast cancer with poly(d,l-lactide) cisplatin microspheres (PLA-CDDP MSs) by an intratumoral injection technique. PLA-CDDP MSs were prepared by a solvent evaporation process. Breast tumor cells were inoculated into the thighs of rats. After therapy with CDDP or PLA-CDDP MSs (6 mg/kg, subcutaneously, single injection), the tumor volume and blood chemistry of breast tumor-bearing rats were measured and compared daily with those of a control group given saline alone for 16 days. A group of rats were administered [131I]IMISO (50 μCi per rat, intravenously, n = 3) on day 5 and planar scintigraphy was then acquired at 2 h after injection. The percentage of tumor uptake (region of interest) was quantitated by a computer image analyzer and expressed as percentage of injected dose (ID) per pixel. PLA-CDDP microspheres (50-100 (Jim) contained 40.04% (w/w) cisplatin and produced sustained-release properti...

Potential Breast Tumor Imaging Agents: Fluorotamoxifen and Derivatives

This study is aimed at developing a ligand to be used for imaging estrogen receptor positive breast tumors by Positron Emission Tomography (PET). We describe the synthesis of fluorotamoxifen analogs with the fluorine atom positioned on the aliphatic side chain of tamoxifen and the measurement of the in vitro binding of fluorotamoxifens to estrogen receptors. N,N-Diethylfluorotamoxifen was prepared from the tosyl ester of the corresponding hydroxy derivative. 18F-Labeled N,N-diethylfluoromethyltamoxifen was prepared in 60% yield. These studies indicate that fluorinated tamoxifens have high affinity for estrogen receptors and can be labeled with 18F, thus reflecting a potential for use in imaging estrogen receptors by PET.