Optimizing the amino terminal Cu(II)- and Ni(II)-binding (ATCUN) motif for Cu(II) complexes with improved inertness

Area of Science:

• Inorganic Chemistry
• Radiochemistry
• Biochemistry

Background:

• Copper(II) complexes are vital for medical imaging, particularly ⁶⁴Cu positron emission tomography (PET).
• The stability of these complexes directly impacts their efficacy and safety in diagnostic procedures.
• The amino terminal Cu(II)- and Ni(II)-binding (ATCUN) motif is a common structural element in copper-binding peptides.

Purpose of the Study:

• To investigate methods for enhancing the inertness and stability of copper(II) complexes.
• To evaluate the impact of specific amino acid substitutions within the ATCUN motif on complex stability.
• To identify key positions within the ATCUN motif that influence copper(II) binding and complex stability.

Main Methods:

• Sequence analysis of the ATCUN motif with various amino acid substitutions.
• Assessment of copper(II) and nickel(II) binding affinities.
• Evaluation of complex inertness and stability under relevant conditions.

Main Results:

• Introducing a tryptophan at position 4 of the ATCUN motif significantly improved complex inertness.
• Amino acid at position 2 exerted a stronger influence on complex stability compared to position 1.
• Specific sequence modifications can be tailored to optimize copper complex performance.

Conclusions:

• Strategic amino acid substitutions, particularly tryptophan at position 4, can enhance the stability of copper(II) complexes.
• Position 2 is a critical determinant for modulating the stability of ATCUN-based copper complexes.
• These findings offer a pathway for developing more robust copper complexes for PET imaging and other applications.