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

Luoto, Pauliina; Suilamo, Sami; Oikonen, Vesa; Arponen, Eveliina; Helin, Semi; Herttuainen, Jukka; Hietamäki, Johanna; Holopainen, Aila; Kailajärvi, Marita; Peltonen, Juha; Rouru, Juha; Sallinen, Jukka; Scheinin, Mika; Virta, Jere; Virtanen, Kirsi; Volanen, Iina; Roivainen, Anne; Rinne, Juha

Purpose: C-labelled 1-[( S)-1-(2,3-dihydrobenzo[1,2]dioxin-2-yl)methyl]-4-(3-methoxy-methylpyridin-2-yl)-piperazine (C-ORM-13070) is a novel PET tracer for imaging of α-adrenoceptors in the human brain. Brain α-adrenoceptors may be therapeutic targets in several neuropsychiatric disorders, including depression, schizophrenia and Alzheimer's disease. To validate the use of 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 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 C-ORM-13070 and radiation exposure were investigated by dynamic PET/CT imaging without blood sampling. Results: Two radioactive metabolites of C-ORM-13070 were detected in human arterial plasma. The proportion of unchanged 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 C-ORM-13070 in arterial plasma were 0.0117 ± 0.0056 min 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: C-ORM-13070 was rapidly metabolized in human subjects after intravenous injection. The effective radiation dose of C-ORM-13070 was in the same range as that of other C-labelled brain receptor tracers. An injection of 500 MBq of C-ORM-13070 would expose a subject to 2.0 mSv of radiation. This supports the use of C-ORM-13070 in repeated PET scans, for example, in receptor occupancy trials with novel drug candidates.

POSITRON emission tomography; LIGANDS (Biochemistry); ADRENERGIC receptors; PHARMACOKINETICS; RADIATION dosimetry

European Journal of Nuclear Medicine & Molecular Imaging, 2014, Vol 41, Issue 10, p1947

1619-7070

Academic Journal

10.1007/s00259-014-2782-y