Tyrosine is an attractive target for chemo- and site-selective protein modification. The particular chemical nature of tyrosine residues allows bioconjugation chemistry with reactive aryl diazonium salts via electrophilic aromatic substitution to produce diazo compounds. In this work, we describe the preparation of ⁶⁴Cu- and ⁶⁸Ga-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)-diazonium salts as building blocks for azo coupling chemistry with tyrosine and tyrosine-containing peptides and proteins under mild conditions. 2-S-(4-aminobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-NH₂-Bn-NOTA) was used to form the corresponding ⁶⁴Cu- and ⁶⁸Ga-labeled complexes, followed by diazotization with NaNO₂ in the presence of HCl. ⁶⁴Cu- and ⁶⁸Ga-labeled NOTA complexes were prepared in high radiochemical yields >80% starting from 20 μg of p-NH₂-Bn-NOTA. Conversion of p-NH₂-Bn-NOTA complexes into diazonium salts followed by azo coupling with l-tyrosine afforded ⁶⁴Cu- and ⁶⁸Ga-labeled tyrosine in radiochemical yields of 80 and 56%, respectively. Azo coupling with tyrosine-containing hexapeptide neurotensin NT(8-13) afforded ⁶⁴Cu- and ⁶⁸Ga-labeled NT(8-13) in radiochemical yields of 45 and 11%, respectively. Azo coupling of ⁶⁴Cu-labeled NOTA-diazonium salt with human serum albumin (HSA) gave ⁶⁴Cu-labeled HSA in radiochemical yields of 20%. The described azo coupling chemistry represents an innovative and versatile bioconjugation strategy for selective targeting of tyrosine residues in peptides and proteins.

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