PIDAZTA: Structurally Constrained Chelators for the Efficient Formation of Stable Gallium-68 Complexes at Physiological pH

Two structurally constrained chelators based on a fused bicyclic scaffold, 4-amino-4-methylperhydro-pyrido[1,2-a][1,4]diazepin-N,N ',N '-triacetic acids [(4R*,10aS*)-PIDAZTA (L1) and (4R*,10aR*)-PIDAZTA (L2)], were designed for the preparation of Ga-III-based radiopharmaceuticals. The stereochemistry of the ligand scaffold has a deep impact on the properties of the complexes, with unexpected [Ga(L2)OH] species being superior in terms of both thermodynamic stability and inertness. This peculiar behavior was rationalized on the basis of molecular modeling and appears to be related to a better fit in size of Ga-III into the cavity of L2. Fast and efficient formation of the Ga-III chelates at room temperature was observed at pH values between 7 and 8, which enables Ga-68 radiolabeling under truly physiological conditions (pH 7.4).