Synthesis and Evaluation of Novel 111 In-Labeled Picolinic Acid-Based Radioligands Containing an Albumin Binder for Development of a Radiotheranostic Platform.

Picolinic acid-based metallic chelators, e.g., neunpa and octapa, have attracted much attention as promising scaffolds for radiotheranostic agents, particularly those containing larger α-emitting radiometals. Furthermore, albumin binder (ALB) moieties, which noncovalently bind to albumin, have been utilized to improve the pharmacokinetics of radioligands targeting various biomolecules. In this study, we designed and synthesized novel neunpa and octapa derivatives (Neunpa-2 and Octapa-2, respectively), which contained a prostate-specific membrane antigen (PSMA)-binding moiety (model targeting vector) and an ALB moiety. We evaluated the fundamental properties of these derivatives as radiotheranostic agents using 111 In. In a cell-binding assay using LNCaP (PSMA-positive) cells, [ 111 In]In-Neunpa-2 and [ 111 In]In-Octapa-2 specifically bound to the LNCaP cells. In addition, a human serum albumin (HSA)-binding assay revealed that [ 111 In]In-Neunpa-2 and [ 111 In]In-Octapa-2 exhibited greater binding to HSA than their non-ALB-conjugated counterparts ([ 111 In]In-Neunpa-1 and [ 111 In]In-Octapa-1, respectively). A biodistribution assay conducted in LNCaP tumor-bearing mice showed that the introduction of the ALB moiety into the 111 In-labeled neunpa and octapa derivatives resulted in markedly enhanced tumor uptake and retention of the radioligands. Furthermore, single-photon emission computed tomography imaging of LNCaP tumor-bearing mice with [ 111 In]In-Octapa-2 produced tumor images. These results indicate that [ 111 In]In-Octapa-2 may be a useful PSMA imaging probe and that picolinic acid-based ALB-conjugated radiometallic complexes may be promising candidates as radiotheranostic agents.