The fluorine atom as a probe for drug monitoring. Chemical synthesis of fluorinated drugs and in vivo studies in animal tumor models.

Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.

The fluorine atom as a probe for drug monitoring. Chemical synthesis of fluorinated drugs and in vivo studies in animal tumor models.

Diss Abstr Int [B]; 54(12):6150 1994. Unique Identifier : AIDSLINE ICDB/95607170
Parti SC; Univ. of Southern California

Abstract: Nuclear medicine imaging technology and nuclear magnetic resonance spectroscopy are two unique methodologies that can be utilized for the detection and analysis of compounds containing the fluorine atom. While the magnetic resonance technology using the naturally occurring fluorine (19F) allows the identification of the chemical nature of the fluorinated compound, the sensitivity in this technique is very low. On the contrary, the nuclear imaging technique using the radioactive isotope (18F) is tremendously sensitive in identifying the presence of fluorine without differentiating between the chemical nature of the compounds involved. New synthetic schemes for preparing 18F-fluorodeoxythymidine (18FDT) and 18F-midazolam to study the biodistribution and targeting of these drugs using positron emission tomography have been developed. Also, noninvasive dynamic measurements of 5-fluorouracil and effects of biochemical modulation with methotrexate in animal and human tumors using NMR spectroscopy have been studied. Fluorodeoxythymidine, a fluorinated analog of azidothymidine (AZT) is significantly more potent than AZT against the HIV virus but also has a narrower selectivity index and high toxicity. To synthesize 18FDT, the 5'-hydroxy group of thymidine was protected with a trityl group, then the 3' hydroxy group was substituted with a mesyl group in the lyxo configuration. Treatment with 18F-potassium fluoride and crown either followed by detritylation of the 5'-position yielded 18FDT within 2 hours with 7% labeling efficiency. Midazolam, a fluorinated imidazobenzodiazepine used as an anesthetic agent shows stronger affinity for the benzodiazepine receptor than classical benzodiazepines like diazepam. 18F-midazolam will allow noninvasive PET studies to monitor the spatial and temporal biodistribution of this drug in the brain. After midazolam was nitrated and reduced at the 5'-position, the 2'-fluorine was displaced by an amine group. Subsequent removal of the 5'-amine resulted in 2'-amino-2'-desfluoromidazolam. Using the Balz-Schiemann reaction, radiolabeled fluorine was introduced replacing the 2'-amine group to yield 18F-midazolam in approximately 1 hour with 18% labeling efficiency. 19F-Magnetic resonance spectroscopy was successfully utilized for noninvasive dynamic measurements of 5-fluorouracil to determine the extent of targeting and metabolism of 5-fluorouracil to its pharmacologically active metabolites and biochemical modulation with methotrexate in rats bearing Walker 256 carcinosarcomas. Methotrexate pretreatment prior to chemotherapy with 5-fluorouracil significantly increased metabolism of 5-FU to fluoronucleotides and high molecular anabolites in Walker 256 tumors. Best results were noted with a 4-hour pretreatment with methotrexate before 5-fluorouracil therapy. (Copies available exclusively from Micrographics Department, Doheny Library, USC, Los Angeles, CA 90089-0182.)

Keywords: Animal Disease Models, Animal *Drug Monitoring Fluorine/*CHEMISTRY Fluorouracil/CHEMISTRY Human Magnetic Resonance Imaging Methotrexate/CHEMISTRY Midazolam/CHEMISTRY Neoplasms/*RADIOGRAPHY Zidovudine/CHEMISTRY THESIS
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