Document Detail

Radiosynthesis and Preclinical Evaluation of 3'-Aza-2'-[18F]Fluorofolic Acid - A Novel PET Radiotracer for Folate Receptor Targeting.
MedLine Citation:
PMID:  23273015     Owner:  NLM     Status:  Publisher    
The folate receptor (FR) has been identified as a valuable target for imaging of cancer and activated macrophages, involved in inflammatory and autoimmune diseases via positron emission tomography (PET). Therefore, conjugates of folic acid have been synthesized by coupling of a radiolabeled prosthetic group to the glutamate part of folic acid (pendent approach). In this work, we present a novel class of folates, where the phenylring of folic acid was isosterically replaced by a pyridine moiety for direct labeling with [18F]fluoride (integrated approach). 3'-Azafolic acid and its 2'-halogenated derivatives (2'-chloro and 2'-fluoro) were evaluated in vitro to determine their binding affinity. 3'-Aza-2'-[18F]fluorofolic acid ([18F]6) was obtained, starting from N2-acetyl-3'-aza-2'-chlorofolic acid di-tert-butylester (2), in a maximum decay corrected radiochemical yield of about 9% in ≥98% radiochemical purity and high specific activities of 35-127 GBq/µmol. Binding affinity to the FR was high (IC50 = 0.8 ± 0.2 nM) and the radiotracer was stable in human plasma over 4 h at 37 °C. No degradation or defluorination was detected after incubation of the radiotracer for 1 h at 37 °C with human and murine liver microsomes and human S9-fraction. In vivo PET imaging and biodistribution studies with mice demonstrated a high and specific uptake in FR-positive KB tumor xenografts (12.59 ± 1.77% ID/g, 90 min p.i.). A high and specific accumulation of radioactivity was observed in the kidneys (57.33 ± 8.40% ID/g, 90 min p.i.) and salivary glands (14.09 ± 0.93% ID/g, 90 min p.i.), which are known to express the FR and non-specific uptake was found in the liver (10.31 ± 1.77% ID/g, 90 min p.i.). Pre-injection of folic acid resulted in a >85% reduced uptake of [18F]6 in FR-positive tissue (xenografts, kidneys, salivary glands). Furthermore, no radioactive metabolites were detected in the blood, urine or tumor tissue, 30 min p.i. These characteristics indicate that this new 18F-labeled 3'-azafolate is an appropriate tool for imaging FR-positive (malignant) tissues.
Simon M Ametamey; Thomas Betzel; Cristina Müller; Viola Groehn; Adrienne Müller; Josefine Reber; Cindy Fischer; Stefanie Kraemer; Roger Schibli
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-12-30
Journal Detail:
Title:  Bioconjugate chemistry     Volume:  -     ISSN:  1520-4812     ISO Abbreviation:  Bioconjug. Chem.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-31     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9010319     Medline TA:  Bioconjug Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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