Radiolabeling folates

Radiolabeled folate provides a powerful tool for folate bioavaHabiUty studies in animals and for diagnostic procedures in humans. Deuteration at the 3- and 5-positions of the central benzene ring of foHc acid (31) was accompHshed by catalytic debromination (47,48) or acid-cataly2ed exchange reaction (49). Alternatively, deuterium-labeled fohc acid (32) was prepared by condensing pteroic acid with commercially available labeled glutamic acid (50). 

Interestingly, after intravenous administration of a radiolabelled folate conjugate ( -In-dium-diethylenetriaminepenta acid (DTPA)-folate) in the rat, the conjugate was rapidly excreted in the urine. Moreover, after intravenous administration to athymic mice with a human tumour cell implant, the radiotracer was not only taken up by the subcutaneous tumour but was also taken up by the kidneys in significant quantities [63], indicating substantial renal selectivity of the folate conjugate. In addition to the kidney, the liver also has a high concentration of the folate-receptor [64]. 

Fluorouracil (5-fluorouracil, 5-FU, Fig. 5) represents an early example of rational drag design in that it originated from the observation that tumor cells, especially from gut, incorporate radiolabeled uracil more efficiently into DNA than normal cells. 5-FU is a fluorinated pyrimidine analog that must be activated metabolically. In the cells 5-FU is converted to 5-fluoro-2>deoxyuridine-monophosphate (FdUMP). This metabolite inhibits thymidilate synthase which catalyses the conversion of uridylate (dUMP) to thymidilate (dTMP) whereby methylenetetrahydrofo-late plays the role of the carbon-donating cofactor. The reduced folate cofactor occupies an allosteric site of... 

Protein-free plasma folate is filtered at the glomerulus and most is reabsorbed by the proximal renal tubules. Consequently, intact urinary folate is only a small percentage of intake. Folate is predominantly excreted by catabolism foUowing cleavage of the C9-N10 bond to produce p-aminobenzoylpolyglutamates, which are then hydrolyzed to monoglutamates and hT-acetylated before excretion. Biliary excretion of folate has been estimated at about 100 Xg/day, but much of this is reabsorbed in an enterohepatic circulation. Fecal losses have been studied by radiolabeling and have been found to be similar in type and quantity to urinary losses. ... 

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