Synthesis and biological evaluation of a lipophilic, fluorine-18-labeled 5-ethynyl-2′-deoxyuridine derivative

• Published in: Journal of labelled compounds & radiopharmaceuticals 2007-06, Vol.50 (7), p.649-655
• Main Authors: Chitneni, Satish K., De Ruymaeker, Tom, Balzarini, Jan, Verbruggen, Alfons M., Bormans, Guy M.
• Format: Article
• Language: English
• Subjects: BCNAs; Biological and medical sciences; Contrast media. Radiopharmaceuticals; gene expression imaging; Medical sciences; PET; Pharmacology. Drug treatments; VZV-tk
• ISSN: 0362-4803; 1099-1344
• DOI: 10.1002/jlcr.1312

The synthesis and preliminary biological evaluation of a lipophilic, fluorine‐18‐labeled 5‐ethynyl‐2′‐deoxyuridine derivative [18F]‐3 is described. Initially, 5‐ethynyl‐2′‐deoxyuridine 5 was synthesized by coupling trimethylsilyl protected acetylene to 5‐iodo‐2′‐deoxyuridine 4, followed by deprotection in alkaline conditions. Compound 5 was then reacted with 4‐(4′‐iodophenyl)phenol to give 5‐[4(4′‐hydroxyphenyl)phenyl]ethynyl‐2′‐deoxyuridine 6. Compound 6 was reacted with BrCH2CH 219/18F as alkylating agent to give stable or radiolabeled 3. The crude products were purified using reversed phase‐high performance liquid chromatography to obtain compound 3 and [18F]‐3 in 33 and 7.4% yield (decay corrected), respectively. The synthesis time to obtain pure [18F]‐3 was about 60 min (starting from BrCH2CH 218F). The specific radioactivity of the tracer was between 74 and 222 GBq/µmol. The log P7.4 of [18F]‐3 was found to be 2.4. However, biodistribution study in normal mice showed low uptake of the tracer in the brain. The affinity of compounds 6 and 3 for varicella‐zoster virus thymidine kinase enzyme (VZV‐TK) was examined in vitro and the results revealed that the fluorinated analog 3 has a poor affinity for the enzyme in contrast to the phenol precursor 6. Copyright © 2007 John Wiley & Sons, Ltd. A 18F‐labeled 5‐ethynyl‐2′‐deoxyuridine ([18F]‐3) derivative is synthesized and evaluated as a substrate for varicella zoster virus thymidine kinase enzyme (VZV‐TK). In contrast to its phenol precursor 6, the fluoroethyl derivative 3 has poor affinity for the enzyme. Biodistribution study in normal mice showed low uptake of the tracer in brain despite fulfilling the theoretical requirements for BBB penetration of such tracers. Copyright © 2007 John Wiley & Sons, Ltd.