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

TL;DR

Researchers developed new chelators for radiopharmaceuticals and found that amide and alcohol versions worked well, while ketone did not.

Contribution

Introduced new TACN-based chelators with amide, alcohol, and ketone arms and evaluated their radiolabeling efficiency and stability.

Findings

Amide and alcohol chelators successfully labeled with [M(CO)3]+ cores, but ketone did not.

Radiometal complexes showed high hydrophilicity and stability in various biological conditions.

Future improvements in labeling yields under milder conditions are needed for practical applications.

Abstract

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 logD7.4 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.

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