Preparation of isotopically labeled ketoglutarates and methods of hyperpolarization through signal amplification by reversible exchange (sabre)

A composition comprising an isotopic mixture of a compound of Formula (I):

• wherein each R1 is independently selected from hydrogen, deuterium, a cation, C1-C6 alkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)C1-C6 alkyl, (heterocycloalkyl)C1-C6 alkyl, (heteroaryl)C1-C6 alkyl, and (aryl)C1-C6 alkyl;
• and
• wherein Xa, Xb, Xc, and Xd are each independently hydrogen or deuterium, and wherein at least 25% of a sum total deuterium and hydrogen atoms defined by Xa+Xb+Xc+Xd are deuterium,
• or a pharmaceutically acceptable salt thereof.

A method of preparing a hyperpolarized ketoglutarate compound comprising:

• (i) providing a SABRE polarization transfer precatalyst;
• (ii) combining the SABRE polarization transfer precatalyst with a ketoglutarate compound, parahydrogen, and optionally a co-ligand in a solvent to form a mixture comprising an active SABRE catalyst;
• and
• (iii) hyperpolarizing the mixture comprising the active SABRE catalyst by exposing the mixture to a magnetic field or radiofrequency excitation to transfer the polarization from parahydrogen to the ketoglutarate compound to form the hyperpolarized ketoglutarate compound.