Hyperpolarized [13C]-2-hydroxyethylpropionate

Excerpt

The signal of nuclear magnetic resonance (NMR) is proportional to the thermal equilibrium polarization of nuclear spins. As a function of magnetic field strength and temperature, the thermal equilibrium polarization is normally very low. For instance, the polarization level (the population difference) is 5 × 10^-6 for ¹H and 1 × 10^-6 for ¹³C at 1.5 T and at body temperature. Because the thermal equilibrium polarization increases proportionally with the magnetic field strength, magnetic resonance imaging (MRI) systems at field strengths of 3–11.7 T have been developed. A totally different approach for increasing the polarization of spins is to create an artificial, non-equilibrium distribution of nuclear spins called the hyperpolarized state (1). In this state, the polarization of spins can be increased by a factor of ~10⁵ compared with that in the thermal equilibrium state. This approach has been used to hyperpolarize a wide range of organic substances containing ¹³C by either parahydrogen-induced polarization (PHIP) (2) or by dynamic nuclear polarization (DNP) (3). The produced ¹³C signal allows for practical medical and diagnostic imaging (4). The potential applications of hyperpolarized ¹³C imaging include vascular imaging, perfusion imaging, catheter tracking and visualization, interventional applications, and metabolic/molecular imaging (1).

The PHIP method increases the nuclear polarization by a chemical reaction of parahydrogen with a substrate containing double or triple bonds (5). In parahydrogen, the two hydrogen nuclei are oriented antiparallel. This is a non-equilibrium state in which the magnetic moments of the hydrogen nuclei cancel mutually (1). The parahydrogen molecule is added as a whole unit onto substrates by rhodium-catalyzed hydrogenation. Then the non-equilibrium spin polarization of parahydrogen is converted to the nuclear polarization of a vicinal ¹³C nucleus by diabatic-adiabatic magnetic field cycling (6, 7) or by radiofrequency (RF) pulses (8, 9). The magnetic field-cycling method involves two consecutive steps. The magnetic field is first suddenly dropped to nearly zero (<10 nT) from a high field value, followed by an adiabatic increase of the magnetic field up to 100 μT (7). By recycling the external magnetic field strength, the proton-carbon spins are brought into the strong coupling regime where the polarization is transferred from parahydrogen to carbon nuclei. The RF pulse sequence method uses the insensitive nuclei enhanced by polarization transfer (INEPT) mechanism to accomplish the polarization transfer between parahydrogen and ¹³C nuclei (8, 9). Currently, polarization levels of 20–30% can be obtained by the PHIP method for a substrate such as 2-hydroxyethylacrylate (1). Its hydrogenated product (2-hydroxyethylpropionate, abbreviated as HP[¹³C]HEPP) can be injected into subjects at a concentration range of 0.3 to 1.2 M in 2–3 ml. The injected HP[¹³C]HEPP can reach hearts and lungs in <10 s in rodents. An estimated concentration is in the range of 2 to 40 mM for the first pass. This provides a reasonable time window to collect signals in major organs and access changes in molecular structures of metabolic process.

A major difference between hyperpolarized ¹³C MRI and conventional MRI is that the magnetization of hyperpolarized ¹³C is created outside the MRI imager in a polarized system (10). Once the hyperpolarization has been created, the polarization will strive to return to the thermal equilibrium level at a rate governed by T₁ relaxation time, which typically ranges from a few seconds to several minutes for ¹³C depending on the functional groups present. The corresponding time window for imaging is approximately a few minutes. Because 1.1% natural abundance of ¹³C produces negligible ¹³C signal, there is as a result virtually no background signal other than noise from the patient and the coil/receiver system. The injected HP[¹³C]HEPP generates a ¹³C signal that is linearly proportional to its concentration (10). In this respect, hyperpolarized ¹³C MRI behaves in a manner similar to modalities such as positron emission tomography (PET) and single-photon emission tomography (SPECT), where the signal amplitude is directly proportional to concentration of the agents. However, PET and SPECT have much higher sensitivities, allowing for detection of tracers at 10^-8 M. The lack of background signal is advantageous in many applications such as angiography and perfusion, in which collection of additional proton images is required to provide anatomic interpretations. The small molecular size of HP[¹³C]HEPP qualifies it as an extracellular fluid (ECF) MRI contrast agent (10), suitable for pharmacokinetic tracing. HP[¹³C]HEPP remains mainly within the vascular bed during the first few circulations in the body. Subsequently, HP[¹³C]HEPP is distributed into the extracellular space and is finally excreted through the kidneys.