The improved syntheses of 5-substituted 2'-[18F]fluoro-2'-deoxy-arabinofuranosyluracil derivatives ([18F]FAU, [18F]FEAU, [18F]FFAU, [18F]FCAU, [18F]FBAU and [18F]FIAU) using a multistep one-pot strategy.

INTRODUCTION: We and others have previously reported a four-step radiosynthesis of a series of 2'-deoxy-2'-[(18)F]fluoro-5-substituted-1-ß-D-arabinofuranosyluracil derivatives including [(18)F]FAU, [(18)F]FEAU, [(18)F]FFAU, [(18)F]FCAU, [(18)F]FBAU and [(18)F]FIAU as thymidine derivatives for tumor proliferation and/or reporter gene expression imaging with positron emission tomography (PET). Although the radiosynthesis has been proven to be reproducible and efficient, this complicated multistep reaction is difficult to incorporate into an automated cGMP-compliant radiosynthesis module for routine production. Recently, we have developed a simple and efficient one-pot method for routine production of [(18)F]FMAU. In this study, we studied the feasibility of radiosynthesizing [(18)F]FAU, [(18)F]FEAU, [(18)F]FFAU, [(18)F]FCAU, [(18)F]FBAU and [(18)F]FIAU using this newly developed method. METHODS: Similar to the radiosynthesis of [(18)F]FMAU, 5-substituted 2'-[(18)F]fluoro-2'-deoxy-arabinofuranosyluracil derivatives ([(18)F]FAU, [(18)F]FEAU, [(18)F]FFAU, [(18)F]FCAU, [(18)F]FBAU and [(18)F]FIAU) were synthesized in one-pot radiosynthesis module in the presence of Friedel-Crafts catalyst TMSOTf and HMDS. RESULTS: This one-pot radiosynthesis method could be used to produce [(18)F]FAU, [(18)F]FEAU, [(18)F]FFAU, [(18)F]FCAU, [(18)F]FBAU and [(18)F]FIAU. The overall radiochemical yields of these tracers varied from 4.1%±0.8% to 10.1%±1.9% (decay-corrected, n=4). The overall reaction time was reduced from 210 min to 150 min from the end of bombardment, and the radiochemical purity was >99%. CONCLUSIONS: The improved radiosyntheses of [(18)F]FAU, [(18)F]FEAU, [(18)F]FFAU, [(18)F]FCAU, [(18)F]FBAU and [(18)F]FIAU have been achieved with reasonable yields and high purity using a multistep one-pot method. The synthetic time has been reduced, and the reaction procedures have been significantly simplified. The success of this approach may make PET tracers [(18)F]FAU, [(18)F]FEAU, [(18)F]FFAU, [(18)F]FCAU, [(18)F]FBAU and [(18)F]FIAU more accessible for preclinical and clinical research.

[18F]FBAU 3',5'-dibenzoate, a lipophilic prodrug, enhances brain uptake of the cell proliferation tracer [18F]FBAU.

INTRODUCTION: 1-(2-deoxy-2-[(18)F]fluoro-beta-D-arabinofuranosyl)-5-bromouracil ([(18)F]FBAU) is a cell proliferation tracer. However, it does not pass readily through the blood-brain barrier. We synthesized a lipophilic prodrug of [(18)F]FBAU that was intended to enhance brain uptake of [(18)F]FBAU to improve the imaging of brain cell proliferation. METHODS: [(18)F]FBAU was synthesized according to the methods described by Alauddin [J Med Chem 39 (1996) 2835-2843]. The prodrug, 1-(2-deoxy-3,5-O-dibenzoyl-2-[(18)F]fluoro-beta-D-arabinofuranosyl)-5-bromouracil ([(18)F]FBAU 3',5'-dibenzoate), was purified from an intermediate of [(18)F]FBAU. Their lipophilicity was determined by performing octanol/water partition coefficient (log P) measurements. In vitro metabolic fates of the prodrug were examined in rat and mouse plasma and brain homogenates. Brain uptake was determined following iv injection of the radiotracers by killing animals at various time points and dissecting and counting the radioactivity accumulation in the various tissues. RESULTS: Values of log P for [(18)F]FBAU 3',5'-dibenzoate and [(18)F]FBAU were 3.95 and -0.35, respectively. In rat plasma, the prodrug was gradually hydrolyzed to [(18)F]FBAU. Thirty minutes after mixing [(18)F]FBAU 3',5'-dibenzoate in the plasma, 25% of the prodrug had been hydrolyzed. The hydrolysis went more slowly in brain homogenates. At 15 min post injection, relative to animals injected with [(18)F]FBAU, brain uptake of radioactivity in animals injected with [(18)F]FBAU 3',5'-dibenzoate was increased by 150% (P=.005) and 78% (P=.037) in rats and mice, respectively. At 60 min post injection, the radioactive contents extracted from the brain were mostly [(18)F]FBAU. CONCLUSION: The synthesized novel prodrug [(18)F]FBAU 3',5'-dibenzoate has enhanced brain uptake in rodents, suggesting it may be useful as an imaging agent for tracing brain cell proliferation.

Evaluation of [76Br]FBAU 3',5'-dibenzoate as a lipophilic prodrug for brain imaging.

[76Br]FBAU is a potential PET tracer for assessing proliferation. This study proposes that [76Br]FBAU 3',5'-dibenzoate has higher blood-brain-barrier permeability than [76Br]FBAU itself and thus might be better suited for applications in the brain. The brain uptake indexes of the two compounds measured after carotid injection (29.6 +/- 13.9 for [76Br]FBAU 3',5'-dibenzoate, versus 10.0 +/- 8.7 for [76Br]FBAU) support this claim. Biodistribution study also showed that the brain accumulation of activity was higher in rats injected with [76Br]FBAU 3',5'-dibenzoate than with [76Br]FBAU (0.119+/-0.023 DUR at 1 h, versus 0.061 +/- 0.006). [76Br]FBAU 3',5'-dibenzoate was relatively stable in rat plasma, gradually being hydrolyzed to [76Br]FBAU exponentially with a calculated half-life of 0.8 h. DNA incorporation of [76Br]FBAU was also confirmed. The results presented support the hypothesis that the 3',5'-dibenzoate can act as a prodrug for FBAU and deliver more radiolabeled nucleoside to the brain.

New molecular complexes of heterocyclic bis-adducts with bacterial lectins: synthesis and structure-activity relationship studies.

A strongly antitumour effect has been discovered for lectins of Bacillus bacteria [Bacillus subtilis 668(1 + 2)IMV, Bacillus polymyxa 102(1 + 2) KGU] and for their molecular complexes with some heterocyclic bis-adducts of unsubstituted benzimidazole and 6-methyluracile for the first time. These were tested on the tumours: Lymphosarcoma Plissa, Sarcoma 45, Carcinosarcoma Yokera 256. A new convenient method for the preparation of the heterocyclic bisadducts of imidazole, benzimidazole, uraciles with 1,1,1-trifluoro-2-bromo-2-chloroethane is described. The reactions are catalysed by the 18-crown-6-complex.

Synthesis and antiviral activity of (E)-5-(2-bromovinyl)uracil and (E)-5-(2-bromovinyl)uridine.

(E)-5-(2-Bromovinyl)uracil (BVU) and (E)-5-(2-bromovinyl)uridine (BVRU) were synthesized starting from 5-formyluracil via (E)-5-(2-carboxyvinyl)uracil or starting from 5-iodouridine via (E)-5-(2-carbomethoxyvinyl)uridine and (E)-5-(2-carboxyvinyl)uridine, respectively. Depending on the choice of the cell system, BVU and BVRU exhibited a marked activity against herpes simplex virus type 1 (HSV-1) in vitro. Although BVU and BVRU were less potent than the reference compound (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), their antiviral activity spectrum was remarkably similar to that of BVDU. The latter findings suggest that BVU and BVRU are metabolically converted to BVDU or a phosphorylated product thereof. In vivo, BVU protected mice against a lethal disseminated HSV-1 infection.