Deuterium I: Back to the Past
Joseph J.H. Ackerman1
1Washington University in St. Louis, St. Louis, MO, United States

Synopsis

Deuterium (2H=D) is a stable, non-toxic isotope of hydrogen, whose use as a 1H-MRI contrast agent was first proposed by Mansfield and Morris in 1982. Alternatively, 2H can be detected directly. Throughout the late 1980s and 1990s, 2H-MR in vivo focused on D2O (heavy water) as a perfusion tracer. However, a 1987 article did report that 2H resonances from metabolic products of administered 2H-labelled substrates (glucose, acetate) could be observed in vivo. Nevertheless, the field went quiet for two decades until a surge of recent activity. This lecture will review the early history and subsequent dormancy of 2H-MRI.

Background

Deuterium, also referred to as heavy hydrogen (2H = D), is a naturally abundant isotope of hydrogen (1H). While the atomic nucleus of 1H consists of a single proton, the atomic nucleus of 2H has both a neutron and a proton. The 2H natural abundance is 0.015% (150 ppm) of all hydrogen. Deuterium is not radioactive; indeed, essentially all deuterium was produced in the Big Bang. Deuterium has seen extensive use as an isotopic tracer species in chemistry, biology, and medicine resulting in a wide array of “inexpensive” deuterated compounds (e.g., 1 kg D2O, $1,400; 10 g [6,6-2H2]glucose, $200; 25 g [2H3]acetate, $270). Deuterium is only slightly toxic and not a health threat except at very high levels.

Deuterium as a Proton MRI Contrast Agent

The first mention of using 2H in MRI was as a 1H contrast agent. In the classic monograph NMR Imaging in Biomedicine by Peter Mansfield and Peter G. Morris (1), the authors wrote:
“Since NMR images are to some extent complementary to X-ray images, the equivalent contrast agent for proton density would be something which substitutes for 1H in water or for 1H in a water-soluble organic molecule. Deuterium would be ideal … With fast imaging methods, time course of … the lack of 1H (if D2O is used) associated with the injected bolus could be monitored.”
A number of researchers have employed 2H in this manner (2-6).

Deuterium MR Properties

The 2H nucleus possesses angular momentum (spin) with principal spin quantum number I = 1 and can be observed directly by standard magnetic resonance methods. The 2H magnetogyric ratio (γ) is 15% that of 1H, leading to a per spin sensitivity at constant field (γ3 I (I +1)) that is ~1% of 1H. Deuterium relaxation is dominated by the interaction of its nuclear electric-quadrupole-moment with the electric field gradient at the nucleus resulting from the local chemical bonds. Fortunately, because the 2H nuclear electric-quadrupole-moment is small (e.g., 30-fold less than that of 23Na), its relaxation properties in vivo are favorable for MR observation: T1 ~30-300 ms, T2 ~20-60 ms, resonance linewidths ~20-30 Hz. Signal-to-noise ratio (SNR) scales as the square root of the number of averages (√N) per unit time, and √N ~ 1/√T1. Thus, the short 2H T1 in vivo allows rapid signal averaging with a SNR per unit time gain that is ~3-10x compared to 1H.

Deuterium MR SNR Challenge

Nevertheless, direct observation of the 2H MR signal in vivo is challenged by low signal amplitude. For example, 2H enrichment to 0.8 molar in a substrate/tracer of interest will yield a 2H MR signal roughly 10-4x the signal from tissue water (recall that tissue water is ~80 molar in equivalent 1H). Researchers in the late 1980s (2, 7-12) through 1990s (13-24) and early 2000s (25, 26) recognized that 2H enrichment could be maximized via administration of “heavy water”, 2H2O = D2O, which is ~110 molar in equivalent 2H. The freely-diffusible (flow-limited) property of D2O when administered in vivo led to many studies employing D2O as a perfusion tracer (ml blood/100 g tissue/min). Interestingly, during one of the earliest such studies (10), investigators reported, as an aside, that narrow-linewidth 2H resonances could be observed following administration of deuterated glucose or acetate, a finding that lay fallow for two decades and has recently been rediscovered, as will be expanded upon by Robin de Graaf in the lecture to follow.

An Idea Ahead of Its Time

Why didn’t 2H MRI “take off” initially? Four issues stood in the way. (i) At the time there was, and still is, a near exclusive focus – academe and commercial – on developing 1H MRI with its high SNR, high resolution, high “speed”, multiple contrasts, and obvious clinical reimbursement promise. (ii) Most MRI scanners were, and are still, only 1H enabled. (iii) There is a general appreciation in the radiological sciences community for the value of “Cartesian images”, much less so for the value of “metabolite images”. (iv) 2H MRI benefits greatly from very high magnetic field scanners, which are expensive and generally found only at major MRI research centers.

Acknowledgements

The author is pleased to acknowledge support of 2H MRI research ongoing through the following contributors at the Washington University School of Medicine, Barnes-Jewish Hospital, and St. Louis Children's Hospital: the Mallinckrodt Institute of Radiology (MIR); the MIR Small-Animal MR Facility; the Small-Animal Cancer Imaging Shared Resource and the Siteman Investment Program of the Alvin J Siteman Cancer Center (an NIH NCI Comprehensive Cancer Center, grant 2P30 CA091842); and the Intellectual and Development Disabilities Research Center (NIH grant ID P50 HD103525).

References

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Proc. Intl. Soc. Mag. Reson. Med. 30 (2022)