Abstract 110: Preclinical evaluation of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[18F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide: A novel pyridazinoindole ligand for PET imaging of TSPO in cancer
Authors: Cheung Yiu-Yin , Buck Jason R. , Nickels Michael L. , Tang Dewei , Manning H. Charles 
Published: May 2015

There exists a continued need for the development of improved positron emission tomography (PET) biomarkers for glioma imaging to aid in tumor diagnosis, inform clinical outcome, and quantify response to therapeutic intervention. Translocator protein (TSPO) expression is elevated in cancer and has been linked with disease progression and diminished survival and tends to be a hallmark of aggressive tumors. Our laboratory has pursued development of TSPO PET ligands as candidates for molecular imaging of glioma, as TSPO ligand binding correlates with tumor grade in this setting.

We report the first exploration of the structure-activity relationship (SAR) around the pyridazinoindole ring and subsequent radiofluorination of a potent and novel pyridazinoindole-based TSPO-selective ligand for cancer imaging. Library and SAR development around the N3 position of the pyridazinoindole scaffold led to the discovery of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (VUIIS8310), a novel TSPO ligand exhibiting a binding affinity comparable to SSR180575, yet bearing a fluorine atom for subsequent radiolabeling with fluorine-18 (18F) to give 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[18F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (18F-VUIIS8310).

Initial production feasibility and radiochemical development were evaluated with microfluidics and subsequently translated to traditional box-based methods. Subsequently, quantitative, preclinical elevation of 18F-VUIIS8310 was conducted in a rat glioma model, given our previous experience in this setting. Glioma-bearing rats were imaged in a microPET system, with dynamic PET acquisitions acquired simultaneously upon tracer injection. PET ligand reversibility and specificity were evaluated by ligand displacement studies that utilized VUIIS8310. 18F-VUIIS8310 exhibited elevated uptake and specific, displaceable binding in tumor, in contrast with normal brain, which exhibited very low uptake. 18F-VUIIS8310 uptake in the tumor, relative to normal brain, reached a tumor-to-normal brain ratio of greater than 10:1. Ex vivo histological analysis of resected tissue correlated well with PET imaging data.

These preclinical studies illuminate 18F-VUIIS8310 as a promising, novel TSPO PET ligand for imaging glioma and potentially other solid tumors. Importantly, the in vivo stability and high signal-to-noise achieved between tumor and surrounding normal brain suggest the potential of this PET ligand for early tumor detection within this setting. Future head-to-head comparisons between this tracer and emerging, potent TSPO ligands (J. Med. Chem. 2013, 56, 3429) are underway.

Citation Format: Yiu-Yin Cheung, Jason R. Buck, Michael L. Nickels, Dewei Tang, H. Charles Manning. Preclinical evaluation of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[18F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide: A novel pyridazinoindole ligand for PET imaging of TSPO in cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 110. doi:10.1158/1538-7445.AM2014-110