Albumin-binding PSMA ligands: Implications for expanding the therapeutic window

James M. Kelly, Alejandro Amor-Coarasa, Shashikanth Ponnala, Anastasia Nikolopoulou, Clarence Williams, Stephen G. DiMagno, John W. Babich

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Despite significant gains in the treatment of metastatic castration-resistant prostate cancer by radioligands targeting prostate-specific membrane antigen (PSMA), 30% of patients never respond to therapy. One possible explanation is insufficient dose delivery to the tumor because of suboptimal pharmacokinetics. We have recently described RPS-063, a trifunctional ligand targeting PSMA with high uptake in LNCaP xenograft tumors but also in kidneys. We aimed to use structural modifications to increase the tumor-to-kidney ratio through increased albumin binding and tumor uptake and reduction of kidney activity. Methods: Four structurally related trifunctional PSMA-targeting small molecules were prepared by either varying the albumin-binding group or inserting a polyethylene glycol 8 linker into a common structure. The compounds were ranked by PSMA affinity and albumin affinity and were radiolabeled with 68Ga and 177Lu. Tissue kinetics were determined in male BALB/C nu/nu mice bearing LNCaP xenograft tumors. Results: Each of the compounds binds PSMA with a half-maximal inhibitory concentration of no more than 10 nM. The albumin-binding group had a minimal effect on PSMA affinity but changed albumin affinity by an order of magnitude. However, the addition of a polyethylene glycol 8 spacer weakened affinity for albumin in each case. Increased affinity for albumin corresponded with delayed blood clearance and modified uptake kinetics in the tumor and kidney. Uptake of 177Lu-RPS-072 (34.9 ± 2.4 %ID/g) and 177Lu-RPS-077 (27.4 ± 0.6 %ID/g) increased up to 24 h after injection, and washout by 96 h was not significant. As a result, the area under the curve (AUC) in the tumor was in the following order: 177Lu-RPS-072 . 177Lu-RPS-077 . 177Lu-RPS-063 . 177Lu-RPS-071. Increased linker length corresponded to more rapid clearance from kidneys. Consequently, the ratio of tumor AUC and kidney AUC was 4.7 ± 0.3 for 177Lu-RPS-072. Conclusion: The tumor AUC and tumor-to-kidney ratio of 177Lu-RPS-072 are significantly enhanced compared with any small molecule investigated in a LNCaP xenograft model to date. In comparison to other PSMA-targeting radioligands that have been evaluated in a PC3-PIP model, activity in kidneys is reduced and activity in tumors compares favorably when the different PSMA expression levels in LNCaP and PC3-PIP cells are considered. RPS-072 therefore exhibits an increased therapeutic index, shows the potential to increase the dose delivered to tumors, and is a highly promising candidate for targeted radioligand therapy.

Original languageEnglish (US)
Pages (from-to)656-663
Number of pages8
JournalJournal of Nuclear Medicine
Volume60
Issue number5
DOIs
StatePublished - May 1 2019
Externally publishedYes

Keywords

  • Albumin binding
  • PSMA
  • Pharmacokinetics
  • Radioligand therapy

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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    Kelly, J. M., Amor-Coarasa, A., Ponnala, S., Nikolopoulou, A., Williams, C., DiMagno, S. G., & Babich, J. W. (2019). Albumin-binding PSMA ligands: Implications for expanding the therapeutic window. Journal of Nuclear Medicine, 60(5), 656-663. https://doi.org/10.2967/jnumed.118.221150