Carazolol standard

For the testing of heart assist devices most animal models of acute cardiac failure that are usually used show certain disadvantages. We therefore developed a new method using the beta-adrenoceptor antagonist carazolol. We administered a bolus injection of 1 mg/kg followed by a continuous infusion of 1 mg/kg/h in adult German 'Landrasse' pigs. Blood pressure, heart rate, cardiac output and maximum left ventricular pressure rise time showed a significant (P < 0.05) reduction of the control value varying between 40% and 59%. The method is suitable for the testing of surgical approaches in heart failure.

Cerebral beta-adrenergic receptors (beta-ARs) play important roles in normal brain and changes of beta-AR expression are associated with several neuropsychiatric illnesses. Given the high density of beta-AR in several brain regions, quantification of beta-AR levels using PET is feasible. However, there is a lack of radiotracers with suitable biological properties and meeting safety requirements for use in humans. We developed a PET tracer for beta-AR by (18) F-fluorination of 1-((9H-carbazol-4-yl)oxy)-3-4(4-((2-(2-(fluoromethoxy)-ethoxy)methyl)-1H-1,2,3-triazol-1-yl)propan-2-ol ((18) F-FPTC). Methods: [(18) F] FPTC was synthesized by Cu(I)-catalyzed alkyne-azide cycloaddition. First, (18) F-PEGylated alkyne was prepared by (18) F-fluorination of the corresponding tosylate. Next (18) F-PEGylated alkyne was reacted with an azidoalcohol derivative of 4-hydroxycarbazol in the presence of the phosphoramidite Monophos as a ligand and Cu(I) as a catalyst. After purification with radio-HPLC, the binding properties of [(18) F FPTC were tested in beta-AR-expressing C6-glioma cells in vitro and in Wistar rats in vivo using microPET. Results: The radiochemical yield of (18) F-PEGylated alkyne was 74%-89%. The click reaction to prepare [(18) F] FPTC proceeded in 10 min with a conversion efficiency of 96%. The total synthesis time was 55 min from the end of bombardment. Specific activities were >120 GBq/mu mol. Propranolol strongly and dose-dependently inhibited the binding of both [I-125]-ICYP and [(18) F]FPTC to C6 glioma cells, with IC50 values in the 50-60 nM range. However, although both FPTC and propranolol inhibited cellular [I-125]ICYP binding, FPTC decreased, [I-125]ICYP uptake by only 25%, whereas propranolol reduced it by 83%. [(18) F]FPTC has the appropriate lipophilicity to penetrate the blood brain barrier (logP + 2.48). The brain uptake reached a maximum within 2 min after injection of 20-25 MBq [(18) F]FPTC. SUV values ranged from 0.4 to 0.6 and were not reduced by propranolol. Cerebral distribution volume of the tracer (calculated from a Logan plot) was increased rather than decreased after propranolol treatment. Conclusion: 'Click chemistry' was successfully applied to the synthesis of [(18) F]FPTC resulting in high radiochemical yields. [(18) F]FPTC showed specific binding in vitro, but not in vivo. Based on the logP value and its ability to block [I-125]ICYP binding to C6 cells, FPTC may be a lead to suitable cerebral beta-AR ligands. (C) 2014 Elsevier Inc. All rights reserved.