Approaches toward the asymmetric total synthesis of (+)-pretazettine and the development of [F-18]-fluorocholine as a radiotracer for the detection of human prostate cancer

As part of an ongoing effort to develop synthetic pathways toward several of the Amaryllidaceae alkaloids, two new asymmetric syntheses have been developed for a key intermediate in the Baldwin synthesis of the alkaloid, pretazettine. Proceeding from the achiral synthons geraniol and 3-butyn-l-ol, these new pathways permit the selective preparation of either enantiomer of the target intermediate, which will allow for the synthesis of either optical series of the target family of alkaloids. In addition, the use of Heck coupling has been explored as a means of improving a troublesome olefination step, at a later stage in that same synthesis. While the Heck methodology allows for high selectivity, yields are generally low, and additional work is necessary to optimize the technique.*; The upregulation of rates of choline uptake and phosphorylation in certain malignancies has motivated the development of choline-derived radiotracers for noninvasive detection of cancer using positron emission tomography (PET). The choline analog [18F]-fluoromethyldimethyl-(2-hydroxyethyl)ammonium chloride (FCH) has been synthesized and screened for its potential as a PET radiotracer. FCH appears to be accumulated and processed in vivo in a manner consitent with the established mechanism for native choline. Early FCH-PET studies in prostate cancer patients showed high accumulation in prostate carcinoma and detection of secondary soft-tissue and osseous metasteses. Additional studies in patients with intraductal breast cancer and anaplastic astrocytoma showed similarly high accumulation and detection of secondary metastatic disease.; A series of 32 structural analogs of FCH have also been prepared and evaluated for uptake in human prostate cancer PC-3 cells. Analysis of the most promising compounds in a murine PC-3 xenograft model has identified several compounds with highly favorable accumulation and biodistribution, which may equal or surpass FCH as clinically useful oncologic probes.*; *Please refer to dissertation for diagrams.