Synthesis and evaluation of 3'-[18F]fluorothymidine-5'-squaryl as a bioisostere of 3'-[18F]fluorothymidine-5'-monophosphate.

The squaryl moiety has emerged as an important phosphate bioisostere with reportedly greater cell permeability. It has been used in the synthesis of several therapeutic drug molecules including nucleoside and nucleotide analogues but is yet to be evaluated in the context of positron emission tomography (PET) imaging. We have designed, synthesised and evaluated 3'-[18F]fluorothymidine-5'-squaryl ([18F]SqFLT) as a bioisostere to 3'-[18F]fluorothymidine-5'-monophosphate ([18F]FLTMP) for imaging thymidylate kinase (TMPK) activity. The overall radiochemical yield (RCY) was 6.7 ± 2.5% and radiochemical purity (RCP) was >90%. Biological evaluation in vitro showed low tracer uptake (<0.3% ID mg-1) but significantly discriminated between wildtype HCT116 and CRISPR/Cas9 generated TMPK knockdown HCT116shTMPK-. Evaluation of [18F]SqFLT in HCT116 and HCT116shTMPK- xenograft mouse models showed statistically significant differences in tumour uptake, but lacked an effective tissue retention mechanism, making the radiotracer in its current form unsuitable for PET imaging of proliferation.

Site-selective measurement of coupled spin pairs in an organic semiconductor.

From organic electronics to biological systems, understanding the role of intermolecular interactions between spin pairs is a key challenge. Here we show how such pairs can be selectively addressed with combined spin and optical sensitivity. We demonstrate this for bound pairs of spin-triplet excitations formed by singlet fission, with direct applicability across a wide range of synthetic and biological systems. We show that the site sensitivity of exchange coupling allows distinct triplet pairs to be resonantly addressed at different magnetic fields, tuning them between optically bright singlet ([Formula: see text]) and dark triplet quintet ([Formula: see text]) configurations: This induces narrow holes in a broad optical emission spectrum, uncovering exchange-specific luminescence. Using fields up to 60 T, we identify three distinct triplet-pair sites, with exchange couplings varying over an order of magnitude (0.3-5 meV), each with its own luminescence spectrum, coexisting in a single material. Our results reveal how site selectivity can be achieved for organic spin pairs in a broad range of systems.

High-performance liquid chromatographic measurement of atenolol: methodology and clinical applications.

A simple high-performance liquid chromatographic method has been developed for the measurement of atenolol in plasma, breast milk, and urine. The sample (250 microliters) is Vortex-mixed for 30 s with approximately 50 mg sodium chloride, 10 mol/L sodium hydroxide solution (50 microliters), internal standard solution (aqueous benzimidazole, 1.69 mumol/L) (50 microliters) and methyl-tert-butyl ether containing 10% (vol/vol) heptafluorobutanol (200 microliters). After centrifugation (9950 X g, 2 min), a portion (100 microliters) of the resulting extract is analysed on a microparticulate (5 micron) silica column using methanol containing 1 mmol/L d-10-camphorsulphonic acid monohydrate as the mobile phase, and the column effluent is monitored by fluorescence detection using an excitation wavelength of 195 nm. A specimen, together with a quality control sample, can be analysed in duplicate within 30 min. The limit of accurate measurement of the assay is 20 micrograms/L, no endogenous sources of interference have been observed and interference from other drugs is minimal.

Atenolol in the treatment of pregnancy-induced hypertension.

1 The pharmacological properties of atenolol suggest its possible usefulness in pregnancy-induced hypertension. The pharmacokinetics of atenolol in the pregnant woman, concentrations in cord blood, and its effects on maternal blood pressure and the foetus, are evaluated. 2 We studied 13 pregnant women with hypertension, most of them uncontrolled on methyldopa. Whole blood concentrations and urinary excretion of the drug were measured over 24 h following a 100 mg dose. Effects on maternal blood pressure, pulse rate and foetal heart rate and cardiotocograph were compared for the 4 days before treatment and the first 4 days of treatment. The birth weights and Apgar scores of the babies were recorded. 2 The pharmacokinetics of atenolol (plasma half-life of about 8 h) in pregnant women do not differ from the findings in the non-pregnant. The levels of atenolol in the cord blood were confirmed as approximately equal to those in the maternal blood. 4 In the ten women in whom blood pressure was assessed a small significant fall in blood pressure was observed. 5 A 5% mean fall in foetal heart rate resulted but in one case was a rate below 120 beats/min recorded. There was no evidence of depression of the stress response of the foetal heart. Apgar scores 5 min post partum were satisfactory. 6 Atenolol appears to be safe for use in hypertensive pregnancies. Its effectiveness as an antihypertensive agent in pregnancy requires further controlled evaluation.