DoE Optimization Empowers the Automated Preparation of Enantiomerically Pure [18F]Talazoparib and its In Vivo Evaluation as a PARP Radiotracer.
Gregory David BowdenSophie StotzJohannes KinzlerChristian GeibelMichael LämmerhoferBernd J PichlerAndreas MaurerPublished in: Journal of medicinal chemistry (2021)
Given the clinical potential of poly(ADP-ribose) polymerases (PARP) imaging for the detection and stratification of various cancers, the development of novel PARP imaging probes with improved pharmacological profiles over established PARP imaging agents is warranted. Here, we present a novel 18F-labeled PARP radiotracer based on the clinically superior PARP inhibitor talazoparib. An automated radiosynthesis of [18F]talazoparib (RCY: 13 ± 3.4%; n = 4) was achieved using a "design of experiments" (DoE) optimized copper-mediated radiofluorination reaction. The chiral product was isolated from the reaction mixture using 2D reversed-phase/chiral radio-HPLC (>99% ee). (8S,9R)-[18F]Talazoparib demonstrated PARP binding in HCC1937 cells in vitro and showed an excellent tumor-to-blood ratio in xenograft-bearing mice (10.2 ± 1.5). Additionally, a favorable pharmacological profile in terms of excretion, metabolism, and target engagement was observed. This synthesis of [18F]talazoparib exemplifies how DoE can enable the radiosyntheses of synthetically challenging radiolabeled compounds of high interest to the imaging community.
Keyphrases
- dna damage
- dna repair
- high resolution
- pet imaging
- induced apoptosis
- mental health
- ms ms
- small molecule
- type diabetes
- mass spectrometry
- oxidative stress
- machine learning
- metabolic syndrome
- young adults
- endoplasmic reticulum stress
- simultaneous determination
- ionic liquid
- social media
- cell proliferation
- adipose tissue
- insulin resistance
- cell death
- high fat diet induced
- quantum dots
- tandem mass spectrometry