Application Note 21
Development of Hyperpolarized Metabolic Contrast Agents Using PASADENA
Eduard Y. Chekmenev,1,2 Pratip Bhattacharya,2 Brian D. Ross2
1. California Institute of Technology, Pasadena, CA 91125 USA
2. Huntington Medical Research Institutes, Pasadena, CA 91105 USA
Nuclear magnetic resonance (NMR) is a powerful method not only for high-resolution structure elucidation methods on atomic and molecular scales, but also for in vivo magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) in biomedicine. Although NMR has a number of benefits for in vivo applications being nonradioactive and nontoxic compared to other imaging modalities, such as positron emission tomography (PET) and computed tomography (CT), the main weakness of NMR method is its relatively low sensitivity compared to the above methods. Low sensitivity is largely determined by poor alignments of the nuclear spins, which contribute to the formation of the NMR signal in a static magnetic field B0. For example, only 10 out of one million proton spins are aligned with respect to the applied magnetic field B0=3 tesla (T) at room temperature (Figure 1). Nuclear spin alignment is even worse for other biologically relevant nuclei with low gyromagnetic ratio, γ, such as 13C and 15N by four and ten times, respectively, compared to protons. In addition to worse nuclear alignment, NMR detection of low-γ nuclei is further exacerbated by lower receptivity, as overall sensitivity usually scales with γ.3 Thus, 13C and 15N are rarely used for direct detection in clinical practice and biomedical in vivo research in general. However, low-γ also yields a much longer spin lattice relaxation time T1 for 13C and 15N since the dominating mechanism of dipole-dipole relaxation results in T1 being inversely proportional to γ.2 As a result, T1 of 13C and especially 15N of some molecular sites can reach several minutes in vivo.1
While conventional in vivo NMR, such long T1 is prohibitively inconvenient for signal recording and signal averaging, it offers unique advantages and opportunities for NMR methods enhanced by hyperpolarization. The goal of hyperpolarization techniques is to increase the nuclear spin alignment from several parts per million (ppm) to the order of unity (Figure 1). Both dynamic nuclear polarization (DNP)2 and parahydrogen and synthesis allow dramatically enhanced nuclear alignment (PASADENA)3,4 have recently5-13 been demonstrated to reach spin polarization of order unity on 13C and 15N sites. This corresponds to a signal enhancement by a factor of ~100,000 on currently utilized MRI scanners. This dramatic signal enhancement brings the sensitivity of 13C and 15N to the realm of research and potentially clinical in vivo tools.
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