Synapse - Imaging of cancer γ-secretase activity using an inhibitor-based PET probe

Imaging of cancer γ-secretase activity using an inhibitor-based PET probe Journal Article

Authors:	Nie, P.; Kalidindi, T.; Nagle, V. L.; Wu, X.; Li, T.; Liao, G. P.; Frost, G.; Henry, K. E.; Punzalan, B.; Carter, L. M.; Lewis, J. S.; Pillarsetty, N. V. K.; Li, Y. M.
Article Title:	Imaging of cancer γ-secretase activity using an inhibitor-based PET probe
Abstract:	Purpose: Abnormal Notch signaling promotes cancer cell growth and tumor progression in various cancers. Targeting gamma-secretase, a pivotal regulator in the Notch pathway, has yielded numerous gamma-secretase inhibitors (GSIs) for clinical investigation in the last 2 decades. However, GSIs have demonstrated minimal success in clinical trials in part due to the lack of specific and precise tools to assess gamma-secretase activity and its inhibition in vivo. Experimental design: We designed an imaging probe based on GSI Semagacestat structure and synthesized the radioiodine-labeled analogues [I-131]- or [I-124]-PN67 from corresponding trimethyl-tin precursors. Both membrane- and cell-based ligand-binding assays were performed using [I-131]-PN67 to determine the binding affinity and specificity for gamma-secretase in vitro. Moreover, we evaluated [I-124]-PN67 by PET imaging in mammary tumor and glioblastoma mouse models. Results: The probe was synthesized through iodo-destannylation using chloramine-T as an oxidant with a high labeling yield and efficiency. In vitro binding results demonstrate the high specificity of this probe and its ability for target replacement study by clinical GSIs. PET imaging studies demonstrated a significant (P < 0.05) increased in the uptake of [I-124]-PN67 in tumors versus blocking or sham control groups across multiple mouse models, including 4T1 allograft, MMTV-PyMT breast cancer, and U87 glioblastoma allograft. Ex vivo biodistribution and autoradiography corroborate these results, indicating gamma-secretase specific tumor accumulation of [I-124]-PN67. Conclusions: [I-124]-PN67 is a novel PET imaging agent that enables assessment of gamma-secretase activity and target engagement of clinical GSIs.
Keywords:	tumors; model; presenilin-1; notch; activation; disease; complex; phase-i; site; modulators
Journal Title:	Clinical Cancer Research
Volume:	27
Issue:	22
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2021-11-15
Start Page:	6145
End Page:	6155
Language:	English
ACCESSION:	WOS:000719879400010
DOI:	10.1158/1078-0432.Ccr-21-0940
PROVIDER:	wos
PMCID:	PMC8610083
PUBMED:	34475100
Notes:	Article -- Source: Wos