The synthesis and evaluation of N1-(4-(2-[18F]-fluoroethyl)phenyl)-N8-hydroxyoctanediamide ([18F]-FESAHA), A PET radiotracer designed for the delineation of histone deacetylase expression in cancer Journal Article

   

Authors:	Zeglis, B. M.; Pillarsetty, N.; Divilov, V.; Blasberg, R. G.; Lewis, J. S.
Article Title:	The synthesis and evaluation of N1-(4-(2-[18F]-fluoroethyl)phenyl)-N8-hydroxyoctanediamide ([18F]-FESAHA), A PET radiotracer designed for the delineation of histone deacetylase expression in cancer
Abstract:	Introduction: Given the significant utility of suberoylanilide hydroxamic acid (SAHA) in chemotherapeutic protocols, a PET tracer that mimics the histone deacetylase (HDAC) inhibition of SAHA could be a valuable tool in the diagnosis, treatment planning and treatment monitoring of cancer. Here, we describe the synthesis, characterization and evaluation of N1-(4-(2-[18F]-fluoroethyl)phenyl)-N8-hydroxyoctanediamide ([18F]-FESAHA), a PET tracer designed for the delineation of HDAC expression in cancer. Methods: FESAHA was synthesized and biologically characterized in vivo and in vitro. [18F]-FESAHA was then synthesized in high radiochemical purity, and the logP and serum stability of the radiotracer were determined. In vitro cellular uptake experiments and acute biodistribution and small-animal PET studies were performed with [18F]-FESAHA in mice bearing LNCaP xenografts. Results: [18F]-FESAHA was synthesized in high radiochemical purity via an innovative one-pot procedure. Enzymatic inhibition assays illustrated that FESAHA is a potent HDAC inhibitor, with IC50 values from 3 nM to 1.7 μM against the 11 HDAC subtypes. Cell proliferation experiments revealed that the cytostatic properties of FESAHA very closely resemble those of SAHA in both LNCaP cells and PC-3 cells. Acute biodistribution and PET imaging experiments revealed tumor uptake of [18F]-FESAHA and substantially higher values in the small intestine, kidneys, liver and bone. Conclusion: The significant non-tumor background uptake of [18F]-FESAHA presents a substantial obstacle to the use of the radiotracer as an HDAC expression imaging agent. The study at hand, however, does present a number of lessons critical to both the synthesis of hydroxamic acid containing PET radiotracers and imaging agents aimed at delineating HDAC expression. © 2011 Elsevier Inc.
Keywords:	pet; hydroxamic acid; histone deacetylase; [18f]-faha; [18f]-fesaha; saha
Journal Title:	Nuclear Medicine and Biology
Volume:	38
Issue:	5
ISSN:	0969-8051
Publisher:	Elsevier Science Inc.
Date Published:	2011-07-01
Start Page:	683
End Page:	696
Language:	English
DOI:	10.1016/j.nucmedbio.2010.12.008
PROVIDER:	scopus
PMCID:	PMC3145497
PUBMED:	21718944
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-79959631545&partnerID=40&md5=77a14277a7aa84f090da87b7cd8f0eef
Notes:	--- - "Export Date: 17 August 2011" - "CODEN: NMBIE" - "Source: Scopus"

https://synapse.mskcc.org/synapse/works/has_related_data_chk/9627