a) New tracer development: Pyruvic acid is the only tracer approved for human studies. We have optimized conditions for polarization in the human polarizer as well as in pre-clinical polarizer/scanner and are routinely using in ongoing research with several models such as: i) LDHAi studies monitoring the lactate/pyruvate as a pharmacodynamics imaging biomarker to help in lead compound identification; ii) monitoring the bioenergetics profiles of prostate cancer xenografts, orthotopic glioblastoma, and pancreatic cancer xenografts and testing the imaging biomarker response to treatments. While these studies are ongoing, we are developing new tracers such as variants of a-ketoglutarate, dimethyl ketoglutarate, esters of succinate. Polarization conditions for these new agents and preliminary in vivo data have been generated. b) In Vitro system to study metabolic flux data: Several tumor cell lines exist for which xenograft models are not feasible. TO study their metabolic profile, an in cell system has been developed and implemented for in vitro studies in cellular incubations with hyperpolarized substrates such as pyruvate, a-ketoglutarate, succinate esters. An NMR bioreactor comprised of a 5 mm NMR tube in a closed loop, with an injection port to receive hyperpolarized substrates with a perfusion system maintained at physiological temperatures in a table top NMR spectrometer has been assembled. Cells are grown in microcarriers to achieve high cell density and in viable conditions are established. Routine experiments are underway. c) De-noising spectral data from metabolic MRI: With hyperpolarization, the sensitivity gap of 4 orders in magnitude has been achieved to enable 13C Magnetic Resonance Spectroscopic Imaging to monitor the metabolic/biochemical profile of tissues. However, any additional gain in sensitivity by post processing of the acquired data is immensely helpful in improving image quality and also identify and quantify low level metabolic fluxes. A de-noising scheme of spectral data using rank matrix reduction and linear prediction has been developed and significant sensitivity enhancement has been realized. This numerical method can be incorporated in pre-clinical and clinical imaging as well as in NMR based metabolomics. d) Clinical Imaging. i) GMP training: One member in RBB has been trained for GMP operations and has received certification. This will be needed for the tracer compounding in clean room for patient studies. A NIH/CC pharmacist and associate have been involved in this and this team of three will be involved in production of clinical doses. ii) RF Coils: We have identified commercial sources for RF coils for torso, head, and prostate imaging and have placed orders and expect them to be delivered within 60 days. ii) Pulse Programs: We have integrated pulse programs needed for 13C MRI with the conventional 1H based anatomic imaging sequences. We have tested them using phantom objects and with experimental animals.
