| Summary: | The present work investigates the potential for enhancing the NMR signals of DNA nucleobases by parahydrogen-based hyperpolarization. Signal amplification by reversible exchange (SABRE) and SABRE in Shield Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH) of selected DNA nucleobases is demonstrated with the enhancement (<i>ε</i>) of <sup>1</sup>H, <sup>15</sup>N, and/or <sup>13</sup>C spins in 3-methyladenine, cytosine, and 6-O-guanine. Solutions of the standard SABRE homogenous catalyst Ir(1,5-cyclooctadeine)(1,3-bis(2,4,6-trimethylphenyl)imidazolium)Cl (“IrIMes”) and a given nucleobase in deuterated ethanol/water solutions yielded low <sup>1</sup>H <i>ε</i> values (≤10), likely reflecting weak catalyst binding. However, we achieved natural-abundance enhancement of <sup>15</sup>N signals for 3-methyladenine of ~3300 and ~1900 for the imidazole ring nitrogen atoms. <sup>1</sup>H and <sup>15</sup>N 3-methyladenine studies revealed that methylation of adenine affords preferential binding of the imidazole ring over the pyrimidine ring. Interestingly, signal enhancements (<i>ε</i>~240) of both <sup>15</sup>N atoms for doubly labelled cytosine reveal the preferential binding of specific tautomer(s), thus giving insight into the matching of polarization-transfer and tautomerization time scales. <sup>13</sup>C enhancements of up to nearly 50-fold were also obtained for this cytosine isotopomer. These efforts may enable the future investigation of processes underlying cellular function and/or dysfunction, including how DNA nucleobase tautomerization influences mismatching in base-pairing.
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