Radiochemistry and Complex Formation of the Cyclen-Derived Chelator DOTI-Me with Mn²⁺, Cu²⁺, Zn²⁺, Ga³⁺, In³⁺, Tb³⁺,...

In this work, we describe the complex formation and radiochemistry of the cyclen-based chelator DOTI-Me bearing four methylimidazole arms. Radiolabeling properties were evaluated for ^52gMn, ⁶⁴Cu, ⁶⁸Ga, ¹¹¹In, ¹⁶¹Tb, and ¹⁷⁷Lu, and DOTI-Me showed distinct differences to the structurally related H₄DOTA. While radiochemical conversions (RCCs) for ^52gMn and ¹¹¹In were comparable to those of H₄DOTA, DOTI-Me was not suited for ⁶⁸Ga. Conversely, quantitative RCCs were achieved for ⁶⁴Cu at ambient temperature, while elevated temperatures were required for complexation with H₄DOTA. For ¹⁶¹Tb and ¹⁷⁷Lu, good but not quantitative RCCs were obtained with DOTI-Me. With the exemption of ⁶⁸Ga³⁺, radiolabeled complexes showed high stability in ligand challenge experiments and in human serum. X-ray analysis of the nonradioactive complexes revealed the formation of 8-coordinate Mn²⁺ and In³⁺ DOTI-Me complexes. Cu²⁺ adopted a unique distorted square-pyramidal 2 + 3 with the neutral DOTI-Me ligand and a Jahn-Teller distorted 4 + 2 coordination geometry for the diprotonated H₂DOTI-Me²⁺ cation, respectively. For Zn²⁺, the complex with HDOTI-Me⁺ showed a distorted 4 + 3 pentagonal bipyramidal geometry. Summarizing, the ligand DOTI-Me may be an interesting alternative to H₄DOTA for ^52gMn, ⁶⁴Cu, ¹¹¹In, ¹⁶¹Tb, and ¹⁷⁷Lu, covering diagnostic as well as therapeutic radionuclides. Further studies of targeted radiopharmaceuticals based on the DOTI-Me scaffold in combination with the set of radiometals presented herein are thus warranted.