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13 results on '"Sharp, T. L."'

1. Sigma-2 selective fluorinated ligands: Synthetic method and optimization of decarbonylation for radiolabeling

Author

Seo, J. W., Chi, D. Y., Luyt, L. G., Wüst, F., Dence, C. S., Sharp, T. L., Mach, R. H., Welch, M. J., and Katzenellenbogen, J. A.

Abstract

Sigma receptors are membrane-bound proteins having high affinities for a variety psychotropic drugs with opiate-type structures. The sigma receptor subtypes, sigma-1 and sigma-2, have different molecular weights and pharmacological roles.1 Many cancer cell lines (breast, melanoma, prostate cancer) express high levels of sigma receptors,2,3 and proliferative tumor cells express much higher levels of sigma-2 receptors than quiescent cells.4,5 Thus, the sigma-2 receptor has been proposed as a suitable target for imaging proliferative tumor cells. While many ligands are selective for the sigma-1 receptor or are nonselective, very few ligands are selective for the sigma-2 receptor. A radiopharmaceutical based on an azabicyclo[3.3.1]nonane framework was developed by Mach,6 who demonstrated that the rhenium surrogate showed exceptional sigma-2 selectivity; later this agent was labeled with technetium-99m by Kung for tissue distribution studies.7 In considering potential fluorine-18 labeled sigma-2 receptor ligands, our attention focused on members of an indole piperidine series, especially 1 (LU 28-179), which is reported to have a remarkably high sigma-2 binding affinity and selectivity.8,9 Figure 1. The structure of indole piperidine ligands and their inhibition constants toward sigma receptors. Target compounds 1 and 2 were prepared in several steps by a route based on a previously described method,7 with modifications making it more efficient for the synthesis of the precursor molecule (3); compounds 1 and 2 showed high binding affinity and good selectivity (6 fold) for the sigma-2 receptor (Figure 1). The preparation of [18F]-labeled indole piperidine [18F]1 was achieved in two steps from a o-nitroaldehyde precursor (3). Aromatic [18F]fluorination was not reproducible when 3 was treated with F-18 fluoride in the presence of Bu4NOH under microwave heating conditions. However, by using F-18, K2CO3 and kryptofix[2.2.2] under microwave heating, we obtained radiochemical yields of 5-50%. The final decarbonylation step with Wilkinson’s catalyst was studied in various solvents. Decarbonylation using dioxane as solvent produced [18F]1, but with toluene, extensive decomposition resulted. Herein, we present the synthesis of precursor 3, optimization of [18F]fluorination, and decarbonylation to produce [18F]Lu 28-179 (Scheme 1). Future work to prepare [18F]1 will be done using an alternate synthetic route.10 Supported by DOE grants 86ER60401 (to JAK) and 84ER60218 (to MJW). Ref) 1. Vilner, B. J. et al. Cancer Res. 55: 408-413 (1995) 2. John, C. S. et al. Cancer Res. 59: 4578-4583 (1999) 3. Quirion, R. et al. Trends Phrmacol. Sci. 13: 85-6 (1992) 4. Mach, R. H. et al. Cancer Res. 57: 156-161 (1997) 5. Wheeler, K. T. et al. Br. J. Cancer 82: 1223-1232 (2000) 6. Mach et al., J. Labelled Cmpds Radiopharm 2001; 44: 899-908 7. Choi, S.-R. Nucle. Med. Biol. 28: 657-666 (2001) 8. Perregaard, J. J. Med. Chem. 38: 1998-2008 (1995) 9. Moltzen, E. K. J. Med. Chem. 38: 2009-2017 (1995) 10. Wüst, F. et al. J. Label. Compd. Radiopharm. 48: 31-43 (2005)

Published
2005

4. Synthesis of an Estrogen Receptor β-Selective Radioligand:  5-[<SUP>18</SUP>F]Fluoro-(2R*,3S*)-2,3-bis(4-hydroxyphenyl)pentanenitrile and Comparison of in Vivo Distribution with 16α-[<SUP>18</SUP>F]Fluoro-17β-estradiol

Author

Yoo, J., Dence, C. S., Sharp, T. L., Katzenellenbogen, J. A., and Welch, M. J.

Abstract

Estrogen receptor β (ERβ), a less active ER subtype that appears to have a restraining effect on the more active ERα, could be a factor that determines the level of estrogen action in certain estrogen target tissues. ERβ is found in breast cancer, and its levels relative to ERα decline with disease progression. Thus, the independent quantification of ERα and ERβ levels in breast cancer by imaging might be predictive of responses to different hormone therapies. To develop an imaging agent for ERβ, we synthesized a fluoroethyl analogue of DPN (2,3-bis(4-hydroxyphenyl)propanonitrile), a known ERβ-selective ligand. This analogue, FEDPN (5-fluoro-(2R*,3S*)-2,3-bis(4-hydroxyphenyl)pentanenitrile), has an 8.3-fold absolute affinity preference for ERβ. [18F]Fluoride-labeled FEDPN was prepared from a toluenesulfonate precursor, which provided [18F]FEDPN with a specific activity greater than 3100 Ci/mmol after HPLC purification. Biodistribution studies in immature female rats using estradiol as a blocking agent revealed specific uptake of [18F]FEDPN in the uterus and ovaries. Experiments using ERα- and ERβ-knockout mice demonstrated the expected ERα-subtype dependence in the tissue uptake of the known 16α-[18F]fluoro-17β-estradiol ([18F]FES), which has a 6.3-fold preference for ERα. The tissue uptake of [18F]FEDPN in the ER knockout mice showed some evidence of mediation by ERβ, but the levels of specific uptake of this agent were relatively modest. Based on our results, imaging of ERα can be done effectively with [18F]FES, but imaging of ERβ will likely require agents with more optimized ERβ binding affinity and selectivity than [18F]FEDNP.

Published
2005

5. MicroPET Imaging of a Gastrin-Releasing Peptide Receptor-Positive Tumor in a Mouse Model of Human Prostate Cancer Using a <SUP>64</SUP>Cu-Labeled Bombesin Analogue

Author

Rogers, B. E., Bigott, H. M., McCarthy, D. W., Manna, D. D., Kim, J., Sharp, T. L., and Welch, M. J.

Abstract

The gastrin-releasing peptide receptor (GRPR) is overexpressed on a variety of carcinomas and has been the target for detection and treatment of these neoplasms in animals. In particular, analogues of the tetradecapeptide bombesin (BN) have been radiolabeled with 99mTc and 111In for detection of GRPR-positive tumors by gamma ray scintigraphy. The goal of this study was to evaluate the potential of the bombesin analogue, DOTA-Aoc-BN(7−14), for positron-emission tomographic (PET) imaging after radiolabeling with the positron-emitter 64Cu. A saturation binding assay on PC-3 human prostate cancer cells showed that 64Cu-DOTA-Aoc-BN(7−14) had an equilibrium binding constant (Kd) of 6.1 ± 2.5 nM and a receptor concentration (Bmax) of 2.7 ± 0.6 × 105 receptors/cell. The radiolabeled analogue also showed rapid internalization with 18.2% internalized into 105 PC-3 cells by 2 h. The tumor localization of 64Cu-DOTA-Aoc-BN(7−14) was 5.5% injected dose per gram in athymic nude mice bearing PC-3 xenografts at 2 h postinjection. The tumor retention with respect to the 2 h value was 76% and 45% at 4 and 24 h, respectively, and was GRPR-mediated as shown by inhibition with a coinjection of excess peptide. MicroPET imaging of 64Cu-DOTA-Aoc-BN(7−14) in athymic nude mice bearing subcutaneous PC-3 tumors showed good tumor localization. Further studies with 64Cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone) (64Cu-PTSM) suggested that low blood flow to the PC-3 tumors may have limited the localization of 64Cu-DOTA-Aoc-BN(7−14). This study demonstrates that 64Cu-DOTA-Aoc-BN(7−14) can be used to detect GRPR-positive tumors by PET imaging.

Published
2003

7. Solubility of 2-Hydroxybenzoic Acid in Select Organic Solvents at 298.15 K

Author

Fina, K. M. De, Sharp, T. L., Roy, L. E., and Acree, W. E., Jr.

Abstract

Experimental solubilities are reported for 2-hydroxybenzoic acid dissolved in 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol, 1-octanol, dibutyl ether, 1,4-dioxane, tetrahydrofuran, ethyl acetate, butyl acetate, 2-propanone, 2-butanone, and cyclohexanone at 298.15 K. Results of these measurements reveal that the observed solubilities in the eight alcohol solvents fall within a fairly narrow mole fraction range of each other. 2-Hydroxybenzoic acid is more soluble in both 1,4-dioxane and tetrahydrofuran than in any of the other alcohol, ester, or ketone solvents studied.

Published
1999

8. Solubility of Anthracene in Ternary 2-Alkoxyethanol + Cyclohexane + Heptane and 2-Alkoxyethanol + Cyclohexane + 2,2,4-Trimethylpentane Solvent Mixtures

Author

Deng, T., Childress, S. D., Fina, K. M. De, Hernandez, C. E., Roy, L. E., Sharp, T. L., and Acree, W. E., Jr.

Abstract

Experimental solubilities are reported for anthracene dissolved in ternary 2-ethoxyethanol + cyclohexane + heptane, 2-ethoxyethanol + cyclohexane + 2,2,4-trimethylpentane, 2-butoxyethanol + cyclohexane + heptane, and 2-butoxyethanol + cyclohexane + 2,2,4-trimethylpentane solvent mixtures at 25 °C. Nineteen compositions were studied for each of the four solvent systems. Results of these measurements are used to test the predictive ability of the ternary solvent form of the combined NIMS/Redlich−Kister equation. Computations showed that the model predicted the observed solubility behavior to within an overall average absolute deviation of about 1.42%.

Published
1999

9. Solubility of Anthracene in Ternary Propanol + Butanol + 2,2,4-Trimethylpentane Solvent Mixtures

Author

Deng, T., Childress, S. D., Fina, K. M. De, Sharp, T. L., and Acree, W. E., Jr.

Abstract

Experimental solubilities are reported for anthracene dissolved in ternary 1-propanol + 1-butanol + 2,2,4-trimethylpentane, 1-propanol + 2-butanol + 2,2,4-trimethylpentane, 2-propanol + 1-butanol + 2,2,4-trimethylpentane, and 2-propanol + 2-butanol + 2,2,4-trimethylpentane solvent mixtures at 25 °C. Nineteen compositions were studied for each of the four solvent systems. Results of these measurements are used to test the predictive ability of the ternary solvent form of the combined NIMS/Redlich−Kister equation. Computations showed that the model predicted the observed solubility behavior to within an overall average absolute deviation of about 0.9%.

Published
1998

12. Tumor uptake of copper-diacetyl-bis(N(4)-methylthiosemicarbazone): effect of changes in tissue oxygenation.

Author

Lewis JS, Sharp TL, Laforest R, Fujibayashi Y, and Welch MJ

Subjects
Animals, Autoradiography, Coordination Complexes, Female, Gliosarcoma diagnostic imaging, Hydralazine pharmacology, Neoplasm Transplantation, Rats, Rats, Inbred F344, Tomography, Emission-Computed, Copper Radioisotopes pharmacokinetics, Gliosarcoma metabolism, Organometallic Compounds pharmacokinetics, Oxygen analysis, Radiopharmaceuticals pharmacokinetics, Thiosemicarbazones pharmacokinetics
Abstract

Unlabelled: We showed previously that, in vitro, copper-diacetyl-bis(N(4)-methylthiosemicarbazone) (Cu-ATSM) uptake is dependent on the oxygen concentration (pO2). We also showed that, in vivo, Cu-ATSM uptake is heterogeneous in animal tumors known to contain hypoxic fractions. This study was undertaken to confirm the pO2 dependence of this selective uptake in vivo by correlating Cu-ATSM uptake with measured tumor pO2., Methods: Experiments were performed with the 9L gliosarcoma rat model using a needle oxygen electrode to measure tissue pO2. Using PET and electronic autoradiography, Cu-ATSM uptake was measured in tumor tissue under various pO2 levels. The oxygen concentration within implanted tumors was manipulated by chemical means or by altering the inhaled oxygen content., Results: A good correlation between low pO2 and high Cu-ATSM accumulation was observed. Hydralazine administration in animals caused a decrease in the average tumor pO2 from 28.61 +/- 8.74 mm Hg to 20.81 +/- 7.54 mm Hg in untreated control animals breathing atmospheric oxygen. It also caused the tumor uptake of Cu-ATSM to increase by 35%. Conversely, in animals breathing 100% oxygen, the average tumor pO2 increased to 45.88 +/-15.9 mm Hg, and the tumor uptake of Cu-ATSM decreased to 48% of that of the control animals. PET of animals treated in a similar fashion yielded time-activity curves showing significantly higher retention of the tracer in hypoxic tissues than in oxygenated tissues., Conclusion: These data confirm that Cu-ATSM uptake in tissues in vivo is dependent on the tissue pO2, and that significantly greater uptake and retention occur in hypoxic tumor tissue. Therefore, the possible use of Cu-ATSM PET as a prognostic indicator in the management of cancer is further validated.

Published
2001

13. Computed radiography versus screen-film radiography: detection of pulmonary edema in a rabbit model that simulates neonatal pulmonary infiltrates.

Author

Don S, Hildebolt CF, Sharp TL, Shackelford GD, Lau DM, Herman TE, and McAlister WH

Subjects
Animals, Animals, Newborn, Observer Variation, Rabbits, Reproducibility of Results, Disease Models, Animal, Pulmonary Edema diagnostic imaging, Tomography, X-Ray Computed statistics & numerical data, X-Ray Intensifying Screens statistics & numerical data
Abstract

Purpose: To determine if computed radiography is equivalent to screen-film radiography in depicting pulmonary edema and to determine if radiation exposure can be reduced with computed radiography while maintaining equivalent diagnostic accuracy for pulmonary edema., Materials and Methods: Oleic acid was intravenously injected into three rabbits at each of four doses: 0, 0.02, 0.04, and 0.06 mL/kg. Two hours later, chest computed radiographs and screen-film radiographs were obtained at 60 kVp and 1.1 mAs. Additional computed radiographs were obtained after reducing milliampere seconds or by reducing milliampere seconds and increasing the kilovolt peak, which reduced bone marrow exposure by up to 20%. The presence of pulmonary opacities, "truth," was established by the wet-dry weight ratio and by chest computed tomography (CT). The radiographs were masked and randomized. Four observers rated the images for the presence of parenchymal opacities with a dichotomous score and judged the quality of the radiographs on a scale from 1 (worst) to 6 (best). Cochran Q tests and McNemar tests were used to analyze the differences in paired comparisons. Image quality was evaluated with logistic regression analysis., Results: There was no significant difference between truth and observer ability to detect opacity for either modality or for any exposure (P > .05). There was no significant difference between computed radiography and screen-film radiography for image quality (P > .05)., Conclusion: Computed radiography is equivalent to screen-film radiography in the detection of pulmonary edema. Radiation exposure reduction of 20% can be achieved without affecting pulmonary edema detection or image quality.

Published
1999
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