Abdallah Cherif

Imaging, biodistribution and therapy potential of Halogenated tamoxifen analogues

Tamoxifen binds to estrogen receptors (ERs) and prevents breast cancer cell proliferation. This study is aimed at developing a ligand for imaging ER (+) breast tumors by positron emission tomography (PET) or single photon emission computed tomography (SPECT). [18F]-Labeled tamoxifen analogue ([18F]FTX) was prepared in 30-40% yield and [131I]-labeled tamoxifen analogue ([131I]ITX) was prepared in 20-25% yield. In mammary tumor-bearing rats, the biodistribution of [18F]FTX at 2 h showed a tumor uptake value (% injected dose/gram tissue) of 0.41 +/- 0.07; when rats were pretreated with diethylstilbestrol (DES), the value changed to 0.24 +/- 0.017. [131I]ITX at 6 h showed a tumor uptake value of 0.26 +/- 0.166; when rats were pretreated with DES, the value changed to 0.22 +/- 0.044. Priming tumor-bearing rats with estradiol, a tumor uptake value for [131I]ITX was increased to 0.48 +/- 0.107 at 6 h. In the [3H]estradiol receptor assay, tumors had a mean estrogen receptor density of 7.5 fmol/mg of protein. In gamma scintigraphic imaging studies with [131I]ITX, the rabbit uterus uptake can be blocked by pretreatment with DES. Both iodo-tamoxifen and tamoxifen reduced ER(+) breast tumor growth at the dose of 50 micrograms in tumor-bearing mice. The findings indicate that tamoxifen analogue uptake in tumors occurs via an ER-mediated process. Both analogues should have potential for diagnosing functioning ER(+) breast cancer.

Development of new markers for hypoxic cells: 131I]Iodomisonidazole and [131I]Iodoerythronitroimidazole

This study was aimed at developing ligands to evaluate tumor hypoxia by planar scintigraphy. Two 2-nitroimidazole analogues were developed as precursor compounds to image hypoxic tumors. Both tosylmisonidazole (Ts MISO) and tosylerythronitroimidazole (Ts ETNIM) were labeled with 131I. The biodistribution and autoradiographic evaluations by planar scintigraphy of 131I-IMISO and 131I-IETNIM were conducted at 1, 2 and 4 hours after administration to rats bearing 13762 breast tumors. Biodistribution of 131I-IMISO was also evaluated in Madison lung tumor-bearing mice. Intratumoral oxygen tension was measured by the Eppendorf system. Biodistribution showed similar tumor/blood and tumor/muscle count density ratios for both compounds. The thyroid uptake of both analogues was increased with time, suggesting in vivo deiodination probably occurred. Autoradiographs of 131I-IMISO and 131I-IETNIM revealed good visualization of the neoplasms. The tumor oxygen tension was 3-6 mmHg as compared to the normal tissue oxygenation of 30-40 mmHg. The findings indicate that these analogues can localize in the hypoxic region of solid tumors and may assist with quantitation of the hypoxic fraction of tumor for proper selection and evaluation of appropriate radiotherapy and chemotherapy.

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.

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.

Evaluation of [131I]iodoerythronitroimidazole as a predictor for the radiosensitizing effect

The aim of this study was to evaluate whether radiolabeled iodoerythronitroimidazole (IETNIM) could predict the radiosensitization effect on tumors. Tumor-bearing mice were irradiated at a dose of 25, 31 and 37 Gy after the injection of IETNIM. They were also exposed to 37 Gy radiation at 35, 70, 140 and 240 min after the i.p. injection of IETNIM. After the irradiation, tumor growth assays were conducted and the effect of IETNIM as a radiosensitizer was estimated as enhancement factor (EF). Tumor uptake was measured at 35, 70, 140 and 240 min after i.p. injection of [131I]IETNIM, which were the same intervals used in the radiosensitization study. EF of IETNIM in mice treated with 25, 30 and 37 Gy irradiation was 0.72, 0.98 and 1.28, respectively. EF of IETNIM in mice irradiated at 35, 70, 140 and 240 min after the injection was 1.50, 1.69, 1.46 and 1.08, which corresponded to the tumor uptake and blood clearance of [131I]IETNIM. [131I]IETNIM may be a suitable radiopharmaceutical to predict the radiosensitization effect of misonidazole analogs on tumors.

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...

Fluorinated Tropinyl Esters for Application with Pet

Muscarinic acetylcholine receptors (MAR) are widely distributed throughout the central nervous system (CNS), the cardiovascular, and the gastrointestinal system, and regulate numerous important physiological functions.1 In the central nervous system (CNS), the majority of cholinergic synapses are muscarinic, and the activation of MAR by acetylcholine appears to play a role in neural mechanisms underlying memory, learning, arousal and the control of movement.2 Deficits in the cholinergic system have been implicated in memory disfunction associated with normal aging and Alzheimer’s disease.3 While studies concerning the number and functional status of MAR in normal aging is equivocal,4 MAR density is decreased in Alzheimer’s disease,5 Parkinson’s disease and Huntington disease. Delineation of muscarinic receptor subtypes on the basis of structure, pharmacology and anatomical location has further suggested that muscarinic receptor subtypes may be differentially affected.5,6 Alterations in MAR also have been noted to occur as a consequence of exposure to various pharmacologically active compounds including muscarinic agonists7 and antagonists,8 organophosphates9 and other acetylcholinesterase inhibitors,10 barbiturates,11 ethanol12 and antidepressants.13