The appropriate treatment strategy for prostatic carcinoma critically depends on its accurate staging. Curative therapy (surgical or radiation therapy) directed at the primary tumor is possible in patients with clinically localized disease. Patients with metastatic disease are, in general, candidates for palliative rather than curative therapy. Current screening techniques for prostate cancer detection (including the prostate specific antigen test) fail to reliably distinguish clinically-localized disease from metastatic disease. A reliable non-invasive method for the detection of prostate cancer metastases would be of immense value to the clinician to a) determine the appropriate treatment plan b) confirm or monitor disease progression. It is the long-range intent of this research to develop a radiotracer for the visualization of prostate cancer metastases in man with either positron emission tomography (PET) or single photon emission computed tomography (SPECT). Most prostate tumors and distant metastases (including those that are resistant to endocrine therapy) express androgen receptors (AR). This proposal will focus on developing gamma- and positron-emitter labeled high affinity, non-steroidal, antiandrogens for application as in vivo AR radioligands. Radioligands will be designed based on the reported structure- activity information of a new series of non-steroidal antiandrogens that display high affinity and selectivity for AR, as exemplified by RU 59063 (Ka = 6.2 nM for human AR). Radiotracer development will involve the following protocol: 1) synthesize ligands and determine their in vitro affinity for the rat AR 2) radiolabel high affinity ligands 3) conduct ex vivo studies in rodents to determine a) their utility as in vivo AR radioligands b) their tumor-localizing ability in athymic nude mice bearing human LNCaP tumor xenografts 4) use either PET or SPECT to determine the imaging capabilities of promising new radioligands in athymic nude mice bearing human LNCaP tumor xenografts. Blood and prostate tissue metabolite analysis will also be conducted for promising radioligands in the rat and tumor-bearing mouse model. On completion, it is expected that this study will provide a radiotracer with suitable characteristics for the visualization of prostate cancer metastases in man. Additional applications that could evolve from this work include: 1) identification of potential radiopharmaceuticals, ([I-131]- or [I-125]labeled), for prostate cancer radiotherapy 2) development of improved antiandrogen drugs for therapeutic use in androgen deprivation therapy.
| Van Dort, Marcian E; Jung, Yong-Woon (2004) Synthesis and structure-activity investigation of iodinated arylhydantoins and arylthiohydantoins for development as androgen receptor radioligands. Bioorg Med Chem Lett 14:5285-8 |
| Van Dort, M E; Jung, Y W (2001) Synthesis and structure-activity studies of side-chain derivatized arylhydantoins for investigation as androgen receptor radioligands. Bioorg Med Chem Lett 11:1045-7 |
| Van Dort, M E; Robins, D M; Wayburn, B (2000) Design, synthesis, and pharmacological characterization of 4-[4, 4-dimethyl-3-(4-hydroxybutyl)-5-oxo-2-thioxo-1-imidazolidinyl]- 2-iodobenzonitrile as a high-affinity nonsteroidal androgen receptor ligand. J Med Chem 43:3344-7 |
