Radiosynthesis of 4-[(18)F]fluoro-L-tryptophan by isotopic exchange on carbonyl-activated precursors.

Several (18)F-labeled aromatic amino acids have been developed primarily for tumor imaging with positron-emission-tomography (PET). Also, (18)F-labeled tryptophan derivatives were synthesized by electrophilic (18)F-fluorination or by introducing a [(18)F]fluoroalkyl group. Here, a 3-step method for a nucleophilic radiosynthesis of 4-[(18)F]fluoro-L-tryptophan was developed. A carbonyl activated precursor containing a chiral amino acid building block was radiofluorinated by isotopic exchange, followed by removal of the activating formyl group by reductive decarbonylation and subsequent cleavage of the building block under acidic conditions. The title compound was obtained within 100 min with a radiochemical yield of about 13%, a molar activity of >70 MBq/mmol and an enantiomeric excess of >99%.

Value and limitations of target-vessel ischemia in predicting late clinical events after drug-eluting stent implantation.

UNLABELLED: Drug-eluting stents reduce clinical events related to restenosis but may be complicated by late stent-thrombosis. Whereas assessment of target-vessel ischemia by myocardial perfusion scintigraphy identifies relevant restenosis noninvasively, it is unknown whether this technique may also predict late clinical events related to late stent-thrombosis and to restenosis after drug-eluting stent implantation. METHODS: All 826 patients treated with stenting between May 2003 and May 2004 were included in the Basel Stent Cost Effectiveness Trial (Basel Stent Kosten-Effektivitäts Trial, or BASKET) and randomized (2:1) to drug-eluting stents or bare metal stents. Myocardial scintigraphy was performed on 476 (64%) of 747 patients without major events after 6 mo. Patients were followed for 1 y for cardiac death, nonfatal myocardial infarction, and target-vessel revascularization due to restenosis or late stent-thrombosis. RESULTS: The rate of target-vessel ischemia in these patients was lower with drug-eluting stents than with bare metal stents (5.4% vs. 10.4%, P = 0.045), similar to the rates of symptom-driven target-vessel revascularization up to 6 mo (4.6% vs. 7.8%, P = 0.08). Ischemia was silent in 68%. During follow-up, patients with target-vessel ischemia had higher event rates than did patients without ischemia (32.4% vs. 6.1%, P < 0.001); however, ischemia did not predict late stent-thrombosis (0/11 cases). CONCLUSION: The rate of clinical restenosis assessed scintigraphically was lower with drug-eluting stents than with bare metal stents and paralleled that of symptom-driven target-vessel revascularization. Target-vessel ischemia independently predicted late clinical events related to restenosis but not to late stent-thrombosis.

Measurement of the nuclear polarization of hydrogen and deuterium molecules using a Lamb-shift polarimeter.

Lamb-shift polarimeters are used to measure the nuclear polarization of protons and deuterons at energies of a few keV. In combination with an ionizer, the polarization of hydrogen and deuterium atoms was determined after taking into account the loss of polarization during the ionization process. The present work shows that the nuclear polarization of hydrogen or deuterium molecules can be measured as well, by ionizing the molecules and injecting the H2(+) (or D2(+)) ions into the Lamb-shift polarimeter.

Image-guided synthesis reveals potent blood-brain barrier permeable histone deacetylase inhibitors.

Recent studies have revealed that several histone deacetylase (HDAC) inhibitors, which are used to study/treat brain diseases, show low blood-brain barrier (BBB) penetration. In addition to low HDAC potency and selectivity observed, poor brain penetrance may account for the high doses needed to achieve therapeutic efficacy. Here we report the development and evaluation of highly potent and blood-brain barrier permeable HDAC inhibitors for CNS applications based on an image-guided approach involving the parallel synthesis and radiolabeling of a series of compounds based on the benzamide HDAC inhibitor, MS-275 as a template. BBB penetration was optimized by rapid carbon-11 labeling and PET imaging in the baboon model and using the imaging derived data on BBB penetration from each compound to feed back into the design process. A total of 17 compounds were evaluated, revealing molecules with both high binding affinity and BBB permeability. A key element conferring BBB penetration in this benzamide series was a basic benzylic amine. These derivatives exhibited 1-100 nM inhibitory activity against recombinant human HDAC1 and HDAC2. Three of the carbon-11 labeled aminomethyl benzamide derivatives showed high BBB penetration (∼0.015%ID/cc) and regional binding heterogeneity in the brain (high in thalamus and cerebellum). Taken together this approach has afforded a strategy and a predictive model for developing highly potent and BBB permeable HDAC inhibitors for CNS applications and for the discovery of novel candidate molecules for small molecule probes and drugs.