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Title: Brain penetrant small molecule 18 F-GnRH receptor (GnRH-R) antagonists: Synthesis and preliminary positron emission tomography imaging in rats

Authors:
ORCiD logo; ORCiD logo; ; ; ; ; ; ;
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1324335
Grant/Contract Number:
SL0002061
Resource Type:
Journal Article: Publisher's Accepted Manuscript
Journal Name:
Nuclear Medicine and Biology
Additional Journal Information:
Journal Volume: 43; Journal Issue: 8; Related Information: CHORUS Timestamp: 2017-10-04 16:43:17; Journal ID: ISSN 0969-8051
Publisher:
Elsevier
Country of Publication:
United Kingdom
Language:
English

Citation Formats

Olberg, Dag E., Bauer, Nadine, Andressen, Kjetil W., Hjørnevik, Trine, Cumming, Paul, Levy, Finn O., Klaveness, Jo, Haraldsen, Ira, and Sutcliffe, Julie L. Brain penetrant small molecule 18 F-GnRH receptor (GnRH-R) antagonists: Synthesis and preliminary positron emission tomography imaging in rats. United Kingdom: N. p., 2016. Web. doi:10.1016/j.nucmedbio.2016.05.003.
Olberg, Dag E., Bauer, Nadine, Andressen, Kjetil W., Hjørnevik, Trine, Cumming, Paul, Levy, Finn O., Klaveness, Jo, Haraldsen, Ira, & Sutcliffe, Julie L. Brain penetrant small molecule 18 F-GnRH receptor (GnRH-R) antagonists: Synthesis and preliminary positron emission tomography imaging in rats. United Kingdom. doi:10.1016/j.nucmedbio.2016.05.003.
Olberg, Dag E., Bauer, Nadine, Andressen, Kjetil W., Hjørnevik, Trine, Cumming, Paul, Levy, Finn O., Klaveness, Jo, Haraldsen, Ira, and Sutcliffe, Julie L. Mon . "Brain penetrant small molecule 18 F-GnRH receptor (GnRH-R) antagonists: Synthesis and preliminary positron emission tomography imaging in rats". United Kingdom. doi:10.1016/j.nucmedbio.2016.05.003.
@article{osti_1324335,
title = {Brain penetrant small molecule 18 F-GnRH receptor (GnRH-R) antagonists: Synthesis and preliminary positron emission tomography imaging in rats},
author = {Olberg, Dag E. and Bauer, Nadine and Andressen, Kjetil W. and Hjørnevik, Trine and Cumming, Paul and Levy, Finn O. and Klaveness, Jo and Haraldsen, Ira and Sutcliffe, Julie L.},
abstractNote = {},
doi = {10.1016/j.nucmedbio.2016.05.003},
journal = {Nuclear Medicine and Biology},
number = 8,
volume = 43,
place = {United Kingdom},
year = {Mon Aug 01 00:00:00 EDT 2016},
month = {Mon Aug 01 00:00:00 EDT 2016}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at 10.1016/j.nucmedbio.2016.05.003

Citation Metrics:
Cited by: 2works
Citation information provided by
Web of Science

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  • In this paper, a novel 18F-labeled α,α-disubstituted amino acid-based tracer, 2-amino-5-[ 18F]fluoro-2-methylpentanoic acid ([ 18F]FAMPe), has been developed for brain tumor imaging with a longer alkyl side chain than previously reported compounds to increase brain availability via system L amino acid transport. Both enantiomers of [ 18F]FAMPe were obtained in good radiochemical yield (24–52% n = 8) and high radiochemical purity (>99%). In vitro uptake assays in mouse DBT gliomas cells revealed that ( S)-[ 18F]FAMPe enters cells partly via sodium-independent system L transporters and also via other nonsystem A transport systems including transporters that recognize glutamine. Biodistribution and smallmore » animal PET/CT studies in the mouse DBT model of glioblastoma showed that both ( R)- and ( S)-[ 18F]FAMPe have good tumor imaging properties with the ( S)-enantiomer providing higher tumor uptake and tumor to brain ratios. Finally, comparison of the SUVs showed that ( S)-[ 18F]FAMPe had higher tumor to brain ratios compared to ( S)-[ 18F]FET, a well-established system L substrate.« less
  • Purpose: To establish whether {sup 18}F-3'-deoxy-3'-fluoro-L-thymidine ({sup 18}F-FLT) can monitor changes in cellular proliferation of non-small-cell lung cancer (NSCLC) during radical chemo-radiotherapy (chemo-RT). Methods and Materials: As part of a prospective pilot study, 5 patients with locally advanced NSCLC underwent serial {sup 18}F-FLT positron emission tomography (PET)/computed tomography (CT) scans during treatment. Baseline {sup 18}F-FLT PET/CT scans were compared with routine staging {sup 18}F-FDG PET/CT scans. Two on-treatment {sup 18}F-FLT scans were performed for each patient on Days 2, 8, 15 or 29, providing a range of time points for response assessment. Results: In all 5 patients, baseline lesional uptakemore » of {sup 18}F-FLT on PET/CT corresponded to staging {sup 18}F-FDG PET/CT abnormalities. {sup 18}F-FLT uptake in tumor was observed on five of nine (55%) on-treatment scans, on Days 2, 8 and 29, but not Day 15. A 'flare' of {sup 18}F-FLT uptake in the primary tumor of one case was observed after 2 Gy of radiation (1.22 x baseline). The remaining eight on-treatment scans demonstrated a mean reduction in {sup 18}F-FLT tumor uptake of 0.58 x baseline. A marked reduction of {sup 18}F-FLT uptake in irradiated bone marrow was observed for all cases. This reduction was observed even after only 2 Gy, and all patients demonstrated a complete absence of proliferating marrow after 10 Gy. Conclusions: This proof of concept study indicates that {sup 18}F-FLT uptake can monitor the distinctive biologic responses of epithelial cancers and highly radiosensitive normal tissue changes during radical chemo-RT. Further studies of {sup 18}F-FLT PET/CT imaging during therapy may suggest that this tracer is useful in developing response-adapted RT for NSCLC.« less
  • Two patients with cerebral gliomas were studied with 18F-fluorophenylalanine, newly synthesized by the electrophilic substitution reaction, using positron emission tomography. The tracer accumulated markedly in the tumor lesion and delineated the extent of the lesion. This new tracer will be promising in the diagnosis of gliomas.
  • We have synthesized 21-(/sup 18/F)fluoro-16 alpha-ethyl-19-norprogesterone (FENP), a high affinity ligand for the progesterone receptor, labeled with the positron-emitting radionuclide fluorine-18 (t1/2 = 110 min). The synthesis proceeds in two steps from 21-hydroxy-16 alpha-ethyl-19-norprogesterone and involves (/sup 18/F)fluoride ion displacement of the 21-trifluoromethanesulfonate (21-triflate). This material is purified by HPLC and is obtained in 4-30% overall yield (decay corrected) within 40 min after the end of bombardment to produce (/sup 18/F)fluoride ion. The effective specific activity, determined by competitive radioreceptor binding assays, is 700-1400 Ci/mmol. In vivo, (/sup 18/F)FENP demonstrates highly selective, receptor-mediated uptake by the uterus of estrogen-primed rats;more » the uterus to blood and uterus to muscle ratios were respectively 26 and 16 at 1 h and 71 and 41 at 3 h after injection. The high target tissue selectivity of this uptake suggests that this compound may be useful for the in vivo imaging of progestin target tissues and receptor-rich tumors (such as human breast tumors) by positron emission tomography.« less