Bispidine-based Ligands as Bifunctional Chelators for Radiopharmaceuticals

Novel bispidine skeleton has been extensively designed as bifunctional chelators (BFCs) for their special stereochemical structure and variable dentate numbers. Bispidinebased ligands (BBLs) as BFCs generally integrate the benefits of conventional acyclic and macrocyclic BFCs, demonstrating exceptional radiolabeling kinetics, thermodynamic stability and kinetic inertness for their metal complexes. The accessible inherent spatial asymmetry in bispidine skeleton is well-suited for Jahn-Teller active metal ions, notably Cu(II). Currently, BBLs have already been studied to coordinate with radionuclides such as <sup>52</sup>Mn, <sup>64/67</sup>Cu, <sup>68</sup>Ga, <sup>111</sup>In, <sup>133</sup>La, <sup>177</sup>Lu, <sup>212</sup>Pb, <sup>212/213</sup>Bi, and <sup>225</sup>Ac for radiopharmaceuticals application. Among them, the <sup>64</sup>Cu, <sup>52</sup>Mn, <sup>111</sup>In, <sup>177</sup>Lu, and <sup>225</sup>Ac complexes with BBLs have particularly made significant research progress. In this review, we introduce the synthesis of BBLs and their applications in chelating the above five metallic radionuclides for the development of radiopharmaceuticals are discussed.