| Chapter 1 of this thesis describes the development of potential PET imaging ligands using microwave thermolysis. Work described in this chapter was primarily investigated at Northeastern University under the supervision of Professor Graham B. Jones. The microwave accelerated fluorodenitration reaction using KF/K222, TBAF/THF (DMSO) and anhydrous TBAF is discussed. The applications of such reactions to commercial pharmaceuticals and potential PET imaging agents are demonstrated. In addition, a novel route to access arenes with a fluoro alkyl tether is explored. The development of the tandem Hiyama coupling fluoro alkylation reaction is discussed.Chapter 2 delves into potential applications of the expedited fluorination reactions reported in Chapter 1 to prostate cancer. The studies reported in this section took place in the Harvard Medical School/Beth Israel Deaconess Medical Center (HMS/BIDMC) labs under the supervision of Dr. Changmeng Cai and Dr. Steven P. Balk. Chapter 2 describes studies of intratumoral androgen synthesis, a mechanism of androgen receptor (AR) activation in CRPC. The conversion of cholesterol to androgens such as DHT and testosterone occur with the aid of different enzymes. A systematic study of these enzymes and their effects on AR activity is discussed. Data obtained from this study will be used to validate AR as an imaging target and to develop selective imaging agents for PET scanning.Also at HMS/BIDMC, our group investigated a protein (HIF-1) involved in cell survival, protein synthesis, transcription, cell growth and proliferation. The effects of different drugs such as rapamycin (mTOR inhibitor), metformin (originally anti-diabetic drug), and bicalutamide (anti-androgen) on this protein was studied. The results of these experiments,will not be described in detail in this thesis, but have played an enormous role in my training and studies related to prostate cancer.Lastly, I spent six educational months working at Novartis Pharmaceuticals. I was working on developing the SAR of potential broad spectrum antibiotics. The details of this project cannot be discussed at this time. |
