[¹⁸⁶Re]Re- and [^99mTc]Tc-Tricarbonyl Metal Complexes with 1,4,7-Triazacyclononane-Based Chelators Bearing Amide, Alcohol, or Ketone Pendent Groups

1,4,7-Triazacyclononane (TACN)-based chelators, such as NOTA and NODAGA, have shown great promise as bifunctional chelators for [M(CO)₃]⁺ cores (M = ^99mTc and ¹⁸⁶Re) in radiopharmaceutical development. Previous investigations of TACN-based chelators bearing pendent acid and ester arms demonstrated the important role the pendent arms have in successful coordination of the [M(CO)₃]⁺ core with the TACN backbone nitrogens. In this work, we introduce three TACN-based bifunctional chelators bearing amide, alcohol, and ketone pendent arms and evaluate their (radio)labeling efficiency with the [M(CO)₃]⁺ core as well as the in vitro stability and hydrophilicity of the resulting radiometal complexes. Following their synthesis and characterization, the amide (2) and alcohol (3) chelators were successfully labeled with the [M(CO)₃]⁺ cores (M = ^natRe, ^99mTc, and ¹⁸⁶Re), while the ketone (4) was not successfully labeled. Radiometal complexes M-2 and M-3 demonstrated hydrophilic character in logD_7.4 studies as well as excellent stability in phosphate-buffered saline (pH 7.4), l-histidine, l-cysteine, and rat serum at 37 °C through 24 h. While the hydrophilicity and stability of these radiocomplexes are attractive, future TACN chelator design modifications to increase radiolabeling yields under milder reaction conditions would improve their potential for use in development of [M(CO)₃]⁺ radiopharmaceuticals.