Synthesis and Preclinical Evaluation of [18F]SiFA-PSMA Inhibitors in a Prostate Cancer Model

Justin J Bailey; Melinda Wuest; Michael Wagner; Atul Bhardwaj; Carmen Wängler; Bjoern Wängler; John F Valliant; Ralf Schirrmacher; Frank Wuest

doi:10.1021/acs.jmedchem.1c00812

Synthesis and Preclinical Evaluation of [¹⁸F]SiFA-PSMA Inhibitors in a Prostate Cancer Model

J Med Chem. 2021 Nov 11;64(21):15671-15689. doi: 10.1021/acs.jmedchem.1c00812. Epub 2021 Oct 21.

Authors

Justin J Bailey¹, Melinda Wuest¹, Michael Wagner¹, Atul Bhardwaj¹, Carmen Wängler², Bjoern Wängler², John F Valliant³, Ralf Schirrmacher¹, Frank Wuest¹

Affiliations

¹ Department of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta T6G 1Z2, Canada.
² Clinic of Radiology and Nuclear Medicine, Biomedical Chemistry and Clinic of Radiology and Nuclear Medicine, Molecular Imaging and Radiochemistry, Medical Faculty Mannheim of Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim 68167, Germany.
³ Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street, Hamilton, Ontario L8S 4K1, Canada.

PMID: 34672630
DOI: 10.1021/acs.jmedchem.1c00812

Abstract

Positron emission tomography (PET) imaging of prostate-specific membrane antigen (PSMA) with gallium-68 (⁶⁸Ga) and fluorine-18 (¹⁸F) radiotracers has aroused tremendous interest over the past few years. The use of organosilicon-[¹⁸F]fluoride acceptors (SiFA) conjugated to urea-based peptidomimetic PSMA inhibitors provides a "kit-like" multidose synthesis technology. Nine novel ¹⁸F-labeled SiFA-bearing PSMA inhibitors with different linker moieties were synthesized and analyzed for their in vitro binding against [¹²⁵I]I-TAAG-PSMA in LNCaP cells. IC₅₀ values ranged from 58-570 nM. Among all compounds, [¹⁸F]SiFA-Asp₂-PEG₃-PSMA (IC₅₀ = 125 nM) showed the highest tumor uptake in LNCaP tumors (SUV_60min 0.73). A substantial increase in molar activity (A_m) (from 7.5 ± 0.5 to 86 ± 3 GBq/μmol) led to a significant increase in LNCaP tumor uptake (SUV_60min 1.18; Δ 0.45 corresponding to +62%). In vivo blocking with DCFPyL resulted in -32% uptake after 60 min. The SiFA-isotopic exchange chemistry offers a method that is readily adaptable for a "kit-type" labeling procedure and clinical translation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Dose-Response Relationship, Drug
Fluorine Radioisotopes
Humans
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Molecular Structure
Neoplasms, Experimental / diagnostic imaging
Neoplasms, Experimental / metabolism
Positron-Emission Tomography*
Prostate-Specific Antigen / analysis
Prostate-Specific Antigen / antagonists & inhibitors*
Prostate-Specific Antigen / metabolism
Prostatic Neoplasms / diagnostic imaging*
Prostatic Neoplasms / metabolism
Radiopharmaceuticals / chemical synthesis
Radiopharmaceuticals / chemistry
Radiopharmaceuticals / pharmacology*
Structure-Activity Relationship
Urea / analogs & derivatives*
Urea / chemical synthesis
Urea / chemistry
Urea / pharmacology

Substances

Fluorine Radioisotopes
PSMA I&T
Radiopharmaceuticals
Urea
Prostate-Specific Antigen
Fluorine-18