Kryptofix® products

An important advance in PET related chemistry was achieved by Welch and Wolf and their coworkers,388,389 who were able to use the K18F/2.2.2-kryptofix combination for aromatic nucleophilic substitution of activated aromatic rings, which could serve as starting materials for more complex products. Welch and coworkers started with nitrobenzalde-hyde, which was converted to [18F]fluorobenzaldehyde making eventually [18F]fluorodexetimide 62 (equation 224) which acts as a muscarinic acetylcholine receptor (mAchR) antagonist. It was used for PET brain studies since acetylcholine receptors are... 

A cartridge was charged with the Step 7 product dissolved in acetonitrile containing kryptofix, potassium carbonate, and [ F]-fluoride. The mixture was then heated to 85 °C for 10 minutes and filtered. The solution was passed onto a Cig solid-phase extraction cartridge and washed with water to remove acetonitrile, kryptofix, and potassium carbonate. Additional acetonitrile was used to wash the radiofluorinated agent off the extraction cartridge, and the product was isolated. 

This is an 18F-labeled pyridaben derivative that binds to mitochondrial complex I of the electron transport chain with high affinity. It is prepared by mixing dry 18F-containing Kryptofix 2.2.2 with BMS-747155-01 in dry acetonitrile and heating at 90°C for 10 min (Huisman et al, 2008). The product is then purified further by HPLC to give an overall radiochemical yield of 50-60% and radiochemical purity of 99%. 

The synthesis of 18F-FET is carried out in two steps (Wester et al, 1999) First, ethylene glycol-1,2-ditosylate in acetonitrile is reacted with dry 18F-containing Kryptofix 2.2.2 and potassium bicarbonate at 90°C for 10 min. The product is purified by absorbing it on a polystyrene cartridge and then eluting with dimethylsulfoxide. Second, the eluate is mixed with dipotassium sodium salt of L-tyrosine and heated at 90°C for 10min. The mixture is purified by HPLC and cation exchange to afford 18F-FET. The radiochemical yield is about 40-45% with purity between 97 and 99%. 

F-FMISO is synthesized in one-step reaction between the protected precursor, l-(2/-nitro-l,-imidazolyl)-2-0-tetrahydropyranyl-3-0-toluenesulfonyl-propanediol (NITTP) and 18F-containing Kryptofix 2.2.2 in acetonitrile solution (Kamarainen et al, 2004). The labeled product is hydrolyzed with acid to give 18F-FMISO, which is further purified by column chromatography using a Sep-Pak cartridge. From an automated synthesis, the radiochemical yield is 34% at EOB after a synthesis time of 50 min. HPLC shows a radiochemical purity of 97%. The molecular structure of 18F-FMISO is shown in Fig. 8.2f. 

F-FAZA is synthesized by nucleophilic substitution reaction between the precursor l-(2,3-di-0-acetyl-5-0-tosyl-a-D-arabinofuranosyl)-2-nitroimida-zole in DMSO solution and 18F-fluoride containing mixture of Kryptofix 2.2.2 and potassium carbonate at 100°C for 5 min (Reischl et al, 2005). The product is hydrolyzed with NaOH solution at 20°C for 2 min, and the solution is neutralized with NaH2PC>4. It is further purified by HPLC and sterilized by 0.22- pm filtration. The radiochemical yield is about 61%. 

Kryptofix 2,2,2 with the diiodide, the ditosylate and the iodotosylate (equation 67), where = 3 or 4. The products were formed in radiochemical yields of between 85 and 95% in 5 minutes. It is interesting that the reaction did not work when = 2 and that the iodide leaving group can be removed exclusively in the presence of the tosylate leaving group. 

DOPO was prepared by reaction of diethyl phosphite with octyl magnesium chloride in refluxing THF and was recrystallized in hexane. Alkyl halides, phase transfer catalysts (SO/HNBU/ TBAH, dicyclohexyl-18 crown-6 (DCHE) and kryptofix [222] and [222 BB]) and solvents were pure grade commercial products. They were used without further purification. Soluble and cross-linked chlorome-thylated polystyrenes (Dow Chemical Co. and Fluka) were purified by dissolution or swelling in chloroform and precipitation in methanol twice before drying under high vacuum. 

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