Synthesis and Evaluation of 11C-Labeled Triazolones as Probes for Imaging Fatty Acid Synthase Expression by Positron Emission Tomography

Cancer cells require lipids to fulfill energetic, proliferative, and signaling requirements. Even though these cells can take up exogenous fatty acids, the majority exhibit a dependency on de novo fatty acid synthesis. Fatty acid synthase (FASN) is the rate-limiting enzyme in this process. Expression and activity of FASN is elevated in multiple cancers, where it correlates with disease progression and poor prognosis. These observations have sparked interest in developing methods of detecting FASN expression in vivo. One promising approach is the imaging of radiolabeled molecular probes targeting FASN by positron emission tomography (PET). However, although [11C]acetate uptake by prostate cancer cells correlates with FASN expression, no FASN-specific PET probes currently exist. Our aim was to synthesize and evaluate a series of small molecule triazolones based on GSK2194069, an FASN inhibitor with IC50 = 7.7 ± 4.1 nM, for PET imaging of FASN expression. These triazolones were labeled with carbon-11 in good yield and excellent radiochemical purity, and binding to FASN-positive LNCaP cells was significantly higher than FASN-negative PC3 cells. Despite these promising characteristics, however, these molecules exhibited poor in vivo pharmacokinetics and were predominantly retained in lymph nodes and the hepatobiliary system. Future studies will seek to identify structural modifications that improve tumor targeting while maintaining the excretion profile of these first-generation 11C-methyltriazolones

Novel Imaging and Therapy Approaches for the Management of Prostate Cancer

Abstract Prostate cancer is the most commonly diagnosed cancer affecting men globally. Despite significant advances in the treatment of advanced prostate cancer, about 30% of patients never respond to first line, FDA-approved treatments such as hormone and chemotherapy. A new treatment strategy is necessary to address the critical and unmet need. Targeting prostate specific membrane antigen (PSMA) in prostate cancer is a valuable approach that can be exploited for diagnostic and therapeutic purposes. In this project, I report the synthesis of trifunctional constructs that comprise three arms: (1) a urea-based moiety with high affinity to PSMA, (2) an albumin binding group with high affinity to human serum albumin, and (3) a chelator to bind to radiometal ions such as 177Lu or 225Ac. The three arms of these ligands were tethered by PEG linkers with different, empirically optimized lengths to construct a generally applicable and tunable drug delivery system. The central hypothesis of this work is that conjugation of the drug to albumin will increase blood circulation time and decrease off-target effects, thereby improving the therapeutic index for targeted radiotherapy. Prostate cancer has a heterogeneous prognosis; many men have an indolent clinical course, while others have aggressive disease. Therefore, discovery of new biomarkers for the identification of aggressive prostate cancer is necessary. Cancer cells require lipids to fulfill energetic, proliferative, and signaling requirements. Extensive expression of FASN in human cancers and its correlation with poor prognosis suggest that fatty acid synthesis provides an advantage for tumor growth, and therefore could be a promising imaging biomarker candidate. One promising approach is the imaging of radiolabeled molecular probes targeting FASN by positron emission tomography (PET). Our aim was to synthesize and evaluate a series of small molecules based on GSK2194069 and BI 99179, as potent FASN inhibitors for FASN PET. These FASN inhibitors were labeled with carbon-11 in good yield and excellent radiochemical purity and evaluated in vitro. Despite the promising in vitro studies, however, these molecules exhibit poor in vivo pharmacokinetics and are predominantly retained in lymph nodes and the hepatobiliary pathway. Future studies will seek to identify structural modifications that maintain tumor targeting while improving the pharmacokinetic profile of these molecules