Towards hyperpolarized 13C-succinate imaging of brain cancer

Abstract

We describe a novel (13)C enriched precursor molecule, sodium 1-(13)C acetylenedicarboxylate, which after hydrogenation by PASADENA (Parahydrogen and Synthesis Allows Dramatically Enhanced Nuclear Alignment) under controlled experimental conditions, becomes hyperpolarized (13)C sodium succinate. Fast in vivo 3D FIESTA MR imaging demonstrated that, following carotid arterial injection, the hyperpolarized (13)C-succinate appeared in the head and cerebral circulation of normal and tumor-bearing rats. At this time, no in vivo hyperpolarized signal has been localized to normal brain or brain tumor. On the other hand, ex vivo samples of brain harvested from rats bearing a 9L brain tumor, 1 h or more following in vivo carotid injection of hyperpolarized (13)C sodium succinate, contained significant concentrations of the injected substrate, (13)C sodium succinate, together with (13)C maleate and succinate metabolites 1-(13)C-glutamate, 5-(13)C-glutamate, 1-(13)C-glutamine and 5-(13)C-glutamine. The (13)C substrates and products were below the limits of NMR detection in ex vivo samples of normal brain consistent with an intact blood-brain barrier. These ex vivo results indicate that hyperpolarized (13)C sodium succinate may become a useful tool for rapid in vivo identification of brain tumors, providing novel biomarkers in (13)C MR spectral-spatial images.

The Blood Oxygen Level–Dependent Functional MR Imaging Signal Can Be Used to Identify Brain Tumors and Distinguish Them from Normal Tissue

“…The functional data had a resolution of 3.75 ϫ 3.75 ϫ 5 mm 3 . Following acquisition of the functional data, a set of 3-mm section thickness high-resolution (256 ϫ 256 pixel matrix size) T1 gadolinium-enhanced images was obtained for functional overlay.…”

“…Over the past several years, tumor enhancement methods have been developed for MR imaging, including the use of contrast agents, fluid-attenuated inversion recovery pulse sequences, 1,2 image-enhancing gases, 3 and recombinant gene technology. 4 Blood oxygen level-dependent functional MR imaging (BOLD fMRI) was originally developed to provide functional information based on cerebral hemodynamic responses during the presentation of a stimulus.…”

“…[20][21][22][23] In this study, we focused on 2 questions: Do brain tumors have a unique BOLD signal intensity, and if so, can we use this signal intensity to distinguish the tumor from the surrounding normal brain? Recent studies have attempted to distinguish brain tumors from normal tissue by using the BOLD fMRI signal intensity; several of these required having animals 3,[24][25][26] or patients 27 breathe carbogen or other hypoxic gases while blood flow was monitored. A more recent study used the BOLD signal intensity itself to distinguish brain tumors from the surrounding edematous tissue.…”

A Hyperpolarizable 1H Magnetic Resonance Probe for Signal Detection 15 Minutes after Spin Polarization Storage

“…Nuclear spin hyperpolarization has evolved as one of most important developments in NMR and MRI in recent years as it starts finding applications in human metabolomics,1, 2, 3, 4 where their detection holds great potential to create tools for the diagnose of diseases. Among the various hyperpolarization techniques,5 dynamic nuclear polarization (DNP)6 and para‐hydrogen‐induced hyperpolarization (PHIP)7 are two of the most popular techniques.…”

“…This requirement is based on observations with DNP and PHIP, techniques that have been used to successfully prepare and detect 13 C‐based magnetization in vivo3, 4 and also show potential for 15 N‐based agents 16. These reported low‐gamma nuclei‐based in vivo studies employ relatively slowly relaxing Zeeman‐derived magnetization in order to overcome the rate of signal loss, but these approaches inherently measure a weaker response than would be provided by 1 H detection, whilst requiring a larger gradient strength for equivalent spatial resolution 17.…”