Abnormal perfusion underlies many leading causes of morbidity and mortality. Stroke (1
), myocardial ischemia (2
), cancer (3
), and pulmonary embolism (4
) are all characterized by changes in local tissue perfusion. Perfusion imaging can play a key role in the management of these and other disorders.
Imaging of perfusion requires the use of a tracer in order to track the flow of blood. Many perfusion imaging techniques make use of exogenous contrast agents for this purpose. A notable exception is arterial spin labeling, which employs the nuclear magnetization of the blood itself as a tracer (5
). The passage of various tracers through tissue is markedly different depending upon the extent to which they can escape from the intravascular space and diffuse through tissue. Agents that can diffuse freely through vessel walls typically exit the vasculature upon reaching the capillary bed and reside in tissue for tens of seconds before they are extracted into the veins. The slow passage of freely diffusible agents allows for the use of slow imaging techniques and enables robust quantification of perfusion. At the other extreme, intravascular and partially permeable agents pass from the arteries to the veins and exit the tissue much more rapidly, requiring the use of faster imaging techniques. Moreover, these agents highlight vessels more than tissue, and provide quantitative perfusion data only after complex modeling of input functions, flow dispersion, permeability, and vascular kinetics.
Existing methods for perfusion imaging can be categorized according to the imaging modality and the type of tracer. Contrast agents for use with PET include 15
O labeled water (6
) or other diffusible 11
C labeled compounds such as butanol (7
). PET techniques provide excellent quantification but limited spatial and temporal resolution. In addition, while both butanol and water are diffusible in tissue, the use of short-lived radioisotopes such as 15
O and 11
C requires a nearby cyclotron. Perfusion imaging with SPECT makes use of contrast agents such as 99m
Tc-hexamethylpropyleneamine oxime (Tc-HMPAO) (8
). Tc-HMPAO is a freely diffusible agent that is converted into a poorly diffusible form by cellular metabolism. SPECT methods based upon this agent have limited spatial resolution, and the ability of this agent to directly assess flow has been questioned (9
). Perfusion imaging with CT can be performed using agents such as iodinated contrast (10
) or xenon (11
). Iodinated contrast is partially permeable and therefore, like all non-diffusible agents, requires detailed modeling in order to obtain quantitative perfusion data. Xenon is diffusible in tissue. However, various methodological challenges (12
) and the radiation dose associated with this method (13
) have limited its widespread use. A variety of contrast mechanisms have been employed for perfusion imaging with MRI. Partially permeable gadolinium contrast agents form the basis for dynamic susceptibility contrast (DSC) perfusion imaging (14
). Again, however, the partial permeability of gadolinium agents introduces various technical challenges. Freely diffusible contrast agents for MR perfusion imaging include water labeled with 17
) and deuterium (16
) and, in the case of arterial spin labeling (ASL), the nuclear magnetization of water protons in flowing blood (5
). ASL offers higher spatial and temporal resolution than PET-based methods. However, the signal-to-noise ratio of ASL perfusion imaging is limited by the small (~1%) signal modulation induced by labeling of arterial water. In addition, the relatively short T1
relaxation time of the water protons prevents the use of ASL in tissues with slow blood flow (17
). A method that could provide large perfusion-induced signal changes from a more slowly decaying, freely diffusible contrast agent would offer clear advantages over existing techniques
Here we propose the use of hyperpolarized freely diffusible 13
C labeled contrast media for MR perfusion imaging. This technique combines many of the advantages of ASL while ameliorating two of its most significant drawbacks, namely its low SNR and the short lifetime of the spin label. Hyperpolarization offers ample signal strength for perfusion imaging, and by choosing a suitable labeled compound it is possible to obtain long T1
relaxation times. Although a variety of small organic molecules labeled with 13
C or 15
N are suitable for use in perfusion imaging, here we focus on 13
C labeled perdeuterated 2-methylpropan-2-ol shown in (this compound is also variously known as dimethylethanol, tertiary butyl alcohol and tert-butanol). Previous work on hyperpolarized perfusion imaging (18
) demonstrated the utility of hyperpolarization for high-resolution imaging, but made use of partially permeable and relatively toxic tracer compounds.
Perdeuterated 13C labeled 2-methylpropan-2-ol. In aqueous solution, the OH group is protonated by exchange.
2-methylpropan-2-ol has several features that make it a particularly attractive agent for perfusion imaging. The toxicity of 2-methylpropan-2-ol is low and has been well documented in the literature. These studies have shown that 2-methylpropan-2-ol is metabolized to form the excretory metabolites t-butanol-glucuronide, 2-methyl-1,2-propanediol, and 2-hydroxyisobutyrate. Its half-life in blood is roughly 5–7 hours (20
). Although the diffusibility of 2-methylpropan-2-ol has not been previously documented in the literature, its octanol-water partition coefficient (log KOW) is 0.35 (22
), indicating a comparable affinity for aqueous and lipid environments and suggesting that it should diffuse freely in tissue. Many other alcohols, including ethanol and n-butanol, are known to be freely diffusible in the brain (23
). In addition, 2-methylpropan-2-ol has long T1
relaxation times when labeled as shown in . Finally, this material can be readily hyperpolarized using dynamic nuclear polarization (DNP) (25
Measurement of 2-methylpropan-2-ol with balanced steady state free precession enables repeated imaging of the bolus passage for an extended period of time. Following a bolus injection, the agent passes slowly through tissue owing to its large distribution volume. The slow bolus passage combined with the long relaxation times of the agent make it possible to image the agent continuously for tens of seconds, thereby enabling extensive signal averaging and robust modeling to extract quantitative estimates of perfusion.