Dynamic Nuclear Polarization
Although in vivo MRI and MRS provide unique anatomical, functional, and biochemical information that aid disease diagnoses, treatment selection, and therapy monitoring, many applications are severely limited by low SNR. Both clinical and preclinical in vivo MRS studies typically require long acquisition times, and, hence, are limited to the investigation of steady-state conditions of tissues and organs. The intrinsic low sensitivity of NMR is the consequence of the low magnetic energies of the nuclear spins compared to the thermal energies of the molecules. This leads to an extreme low degree of polarization (the preferential alignment of the nuclear spins with respect to the external static magnetic field B0). At in vivo temperatures and magnetic field strengths used in preclinical and clinical imaging (0.5T – 15T), the polarization is in the order of a few parts per million. Because the MR signal is proportional to polarization, hyperpolarization, i.e., the creation of nuclear spin polarization well beyond normal thermal equilibrium levels, offers the potential for dramatic SNR enhancement.
Among the methods to hyperpolarize nuclear spins, the most versatile technique is dynamic nuclear polarization (DNP), as the method, in principle, can be used to polarize any nucleus with non integer spin. DNP, first discovered in the 1960s, involves mixing the targeted compound with a free radical (needed as a source of unpaired electrons), placing the mixture in a spectrometer, cooling to 1-2 K, and irradiating with microwaves. By choosing the microwave frequency to coincide with the electron spin resonance, the high degree of electron polarization can be transferred to nearby nuclear spins. The enabling technology for in vivo use, namely the ability to rapidly heat and remove the polarized cryogenically frozen sample via the injection of a hot solvent while maintaining a high level of polarization, is a quite recent development. Once ejected from the polarizer, the sample loses polarization at a rate given by the T1 relaxation time (approx. 1 min for small molecules with 13C-labeled carboxyl groups), and thus must be quickly injected into the subject and scanned. Investigators have reported polarization levels in the liquid state of up to 50% for 13C and 20% for 15N, and because nuclear polarization is maintained through chemical reactions, the observation of not only the injected substrate but also downstream metabolic products is possible.
The leading in vivo hyperpolarized imaging candidate is 13C1-pyruvate, an endogenous substance playing a central role in both catabolic and anabolic metabolism. The search for additional polarizable substrates to probe additional in vivo processes, including oxidative stress and glutamate metabolism, is an active area of research in our laboratory.