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


CONCLUSIONS
(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.
Turku PET Centre, University of Turku and Turku University Hospital, FI-20521, Turku, Finland.
Pauliina
P
Luoto
Sami
S
Suilamo
Vesa
V
Oikonen
Eveliina
E
Arponen
Semi
S
Helin
Jukka
J
Herttuainen
Johanna
J
Hietamäki
Aila
A
Holopainen
Marita
M
Kailajärvi
Juha M
JM
Peltonen
Juha
J
Rouru
Jukka
J
Sallinen
Mika
M
Scheinin
Jere
J
Virta
Kirsi
K
Virtanen
Iina
I
Volanen
Anne
A
Roivainen
Juha O
JO
Rinne
D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging*; D004146:Dioxanes / Q000493:pharmacokinetics*; D006801:Humans; D008024:Ligands; D008297:Male; D010879:Piperazines / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D011485:Protein Binding; D011829:Radiation Dosage; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D014018:Tissue Distribution
C000598340:1-(1-(2,3-dihydrobenzo(1,4)dioxin-2-yl)methyl)-4-(3-methoxymethylpyridin-2-yl)piperazine; D004146:Dioxanes; D008024:Ligands; D010879:Piperazines; D019275:Radiopharmaceuticals; D018341:Receptors, Adrenergic, alpha-2