¹¹C-ORM-13070, a novel PET ligand for brain α2C-adrenoceptors: radiometabolism, plasma pharmacokinetics, whole-body distribution and radiation dosimetry in healthy men.

PURPOSE: (11)C-labelled 1-[(S)-1-(2,3-dihydrobenzo[1,2]dioxin-2-yl)methyl]-4-(3-methoxy-methylpyridin-2-yl)-piperazine ((11)C-ORM-13070) is a novel PET tracer for imaging of α2C-adrenoceptors in the human brain. Brain α2C-adrenoceptors may be therapeutic targets in several neuropsychiatric disorders, including depression, schizophrenia and Alzheimer's disease. To validate the use of (11)C-ORM-13070 in humans, we investigated its radiometabolism, pharmacokinetics, whole-body distribution and radiation dose. METHODS: Radiometabolism was studied in a test-retest setting in six healthy men. After intravenous injection of (11)C-ORM-13070, blood samples were drawn over 60 min. Plasma samples were analysed by radio-HPLC for intact tracer and its radioactive metabolites. Metabolite-corrected plasma time-activity curves were used for calculation of pharmacokinetics. In a separate group of 12 healthy men, the whole-body distribution of (11)C-ORM-13070 and radiation exposure were investigated by dynamic PET/CT imaging without blood sampling. RESULTS: Two radioactive metabolites of (11)C-ORM-13070 were detected in human arterial plasma. The proportion of unchanged (11)C-ORM-13070 decreased from 81 ± 4 % of total radioactivity at 4 min after tracer injection to 23 ± 4 % at 60 min. At least one of the radioactive metabolites penetrated into red blood cells, while the parent tracer remained in plasma. The apparent elimination rate constant and corresponding half-life of unchanged (11)C-ORM-13070 in arterial plasma were 0.0117 ± 0.0056 min(-1) and 73.6 ± 35.8 min, respectively. The organs with the highest absorbed doses were the liver (12 µSv/MBq), gallbladder wall (12 µSv/MBq) and pancreas (9.1 µSv/MBq). The mean effective dose was 3.9 µSv/MBq, with a range of 3.6 - 4.2 µSv/MBq. CONCLUSION: (11)C-ORM-13070 was rapidly metabolized in human subjects after intravenous injection. The effective radiation dose of (11)C-ORM-13070 was in the same range as that of other (11)C-labelled brain receptor tracers. An injection of 500 MBq of (11)C-ORM-13070 would expose a subject to 2.0 mSv of radiation. This supports the use of (11)C-ORM-13070 in repeated PET scans, for example, in receptor occupancy trials with novel drug candidates.

Comparison of triple quadrupole, hybrid linear ion trap triple quadrupole, time-of-flight and LTQ-Orbitrap mass spectrometers in drug discovery phase metabolite screening and identification in vitro--amitriptyline and verapamil as model compounds.

Liquid chromatography in combination with mass spectrometry (LC/MS) is a superior analytical technique for metabolite profiling and identification studies performed in drug discovery and development laboratories. In the early phase of drug discovery the analytical approach should be both time- and cost-effective, thus providing as much data as possible with only one visit to the laboratory, without the need for further experiments. Recent developments in mass spectrometers have created a situation where many different mass spectrometers are available for the task, each with their specific strengths and drawbacks. We compared the metabolite screening properties of four main types of mass spectrometers used in analytical laboratories, considering both the ability to detect the metabolites and provide structural information, as well as the issues related to time consumption in laboratory and thereafter in data processing. Human liver microsomal incubations with amitriptyline and verapamil were used as test samples, and early-phase 'one lab visit only' approaches were used with all instruments. In total, 28 amitriptyline and 69 verapamil metabolites were found and tentatively identified. Time-of-flight mass spectrometry (TOFMS) was the only approach detecting all of them, shown to be the most suitable instrument for elucidating as comprehensive metabolite profile as possible leading also to lowest overall time consumption together with the LTQ-Orbitrap approach. The latter however suffered from lower detection sensitivity and false negatives, and due to slow data acquisition rate required slower chromatography. Approaches with triple quadrupole mass spectrometry (QqQ) and hybrid linear ion trap triple quadrupole mass spectrometry (Q-Trap) provided the highest amount of fragment ion data for structural elucidation, but, in addition to being unable to produce very high-important accurate mass data, they suffered from many false negatives, and especially with the QqQ, from very high overall time consumption.

Equivalent lung deposition of budesonide in vivo: a comparison of dry powder inhalers using a pharmacokinetic method.

AIMS: The aim of this study was to compare lung deposition of budesonide administered from two dry powder inhalers, Giona Easyhaler 200 microg/dose and Pulmicort Turbuhaler 200 microg/dose by utilizing a pharmacokinetic method. METHODS: This was an open, randomized, crossover study in 33 healthy subjects. The study consisted of four treatment periods separated by at least 4 wash-out days. Equivalence in lung deposition was assessed after a single inhaled 1000 microg (5 x 200 microg) dose of budesonide from Giona Easyhaler and from Pulmicort Turbuhaler. Concomitant oral charcoal administration (40 g) was used to prevent gastrointestinal (GI) absorption of budesonide. The efficacy of the charcoal was studied after oral administration of a budesonide 2 mg capsule. The subjects were trained to inhale the study drugs with controlled flow rates, which resulted in an equal pressure drop (4 kPa) across both inhalers. Venous blood samples for the determination of budesonide concentrations in plasma were drawn before and at predetermined time points up to 8 h after drug administration. Budesonide concentrations in plasma were determined using liquid chromatography-tandem mass spectrometry. Several pharmacokinetic parameters were estimated, the area under the budesonide concentration in plasma vs time curve from dosing to infinity (AUC(0, infinity)) being the primary response variable. Equivalence in lung deposition was concluded if the 90% confidence interval (CI) for the Easyhaler : Turbuhaler ratio of AUC(0, infinity) fell within the limits of 0.8-1.25. RESULTS: The mean AUC(0,infinity) value after Easyhaler treatment was 3.48 (standard deviation (SD) 0.93) ng ml(-1) h and after Turbuhaler treatment 3.46 (1.13) ng ml(-1) h. The Easyhaler : Turbuhaler AUC(0, infinity) ratio was 1.02 and the 90% CI was from 0.96 to 1.09. The mean C(max) values (SD) for budesonide in plasma after Easyhaler and Turbuhaler treatments were 1.22 (0.41) ng ml(-1) and 1.29 (0.44) ng ml(-1), respectively. There was no statistically significant difference (P = 0.39) between the median t(max) for Easyhaler (30 min) and Turbuhaler treatment (23 min). Charcoal impaired the GI absorption of budesonide by 96%. The occurrence of adverse events was similar during both treatments. CONCLUSIONS: The results show that the lung deposition of budesonide from Giona Easyhaler 200 microg/dose and Pulmicort Turbuhaler 200 microg/dose dry powder inhalers is equivalent. The charcoal block used to prevent GI absorption of swallowed budesonide was found to be effective.