This thesis studies the design, synthesis, and optimization of radiopharmaceuticals for targeted alpha therapy applications with actinium-225 (225Ac). In Chapter 2, three novel radiopharmaceuticals - 2.1 (DOTA-CCZ-N-Me-α-CycMSH), 2.2 (Macropa-CCZ-N-Me- α-CycMSH), and 2.6 (Macropa-α-CycMSH) for malignant melanoma therapy were labeled with 225Ac and evaluated. All three radiopharmaceuticals exhibited excellent in vitro stability, while Macropa-CCZ-N-Me-α-CycMSH showed lower tumor uptake and moderate normal tissue uptake. In Chapter 3, a total of 5 diaza-18-crown-6 macrocyclic ligands (macropa, macropaquin, macroquin-SO3, macrohopo, and macrohopo’) as chelators for 225Ac were investigated. Two of the chelators (macrohopo and macrohopo’) which contain hydroxypyridinone pendant donor arms are novel and were synthesized/characterized in this work. Macropaquin was able to quantitively radiolabel at chelator concentrations as low as 10-6 M at ambient temperatures within one hour, while chelator macrohopo was unable to achieve 225Ac complexation under any conditions. This thesis showcases the complexity of radiopharmeticuals, in particular for 225Ac
