Coordination Chemistry of Bifunctional Chemical Agents Designed for Applications in 64 Cu PET Imaging for Alzheimer's Disease

• Published in: Inorganic chemistry 2017-11, Vol.56 (22), p.13801-13814
• Main Authors: Sharma, Anuj K, Schultz, Jason W, Prior, John T, Rath, Nigam P, Mirica, Liviu M
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - diagnostic imaging; Alzheimer Disease - metabolism; Amyloid beta-Peptides - metabolism; Animals; Aza Compounds - chemical synthesis; Aza Compounds - chemistry; Aza Compounds - pharmacology; Chelating Agents - chemical synthesis; Chelating Agents - chemistry; Chelating Agents - pharmacology; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Copper; Copper Radioisotopes; Drug Stability; Macrocyclic Compounds - chemical synthesis; Macrocyclic Compounds - chemistry; Macrocyclic Compounds - pharmacology; Peptide Fragments - metabolism; Positron-Emission Tomography; Protein Multimerization; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - pharmacology
• ISSN: 0020-1669; 1520-510X
• DOI: 10.1021/acs.inorgchem.7b01883

Positron emission tomography (PET) is emerging as one of the most important diagnostic tools for brain imaging, yet the most commonly used radioisotopes in PET imaging, C and F, have short half-lives, and their usage is thus somewhat limited. By comparison, the Cu radionuclide has a half-life of 12.7 h, which is ideal for administering and imaging purposes. In spite of appreciable research efforts, high-affinity copper chelators suitable for brain imaging applications are still lacking. Herein, we present the synthesis and characterization of a series of bifunctional compounds (BFCs) based on macrocyclic 1,4,7-triazacyclononane and 2,11-diaza[3.3](2,6)pyridinophane ligand frameworks that exhibit a high affinity for Cu ions. In addition, these BFCs contain a 2-phenylbenzothiazole fragment that is known to interact tightly with amyloid β fibrillar aggregates. Determination of the protonation constants (pK values) and stability constants (log β values) of these BFCs, as well as characterization of the isolated copper complexes using X-ray crystallography, electron paramagnetic resonance spectroscopy, and electrochemical studies, suggests that these BFCs exhibit desirable properties for the development of novel Cu PET imaging agents for Alzheimer's disease.