sup 11^C-ORM-13070, a novel PET ligand for brain [alpha]^sub 2C^-adrenoceptors: radiometabolism, plasma pharmacokinetics, whole-body distribution and radiation dosimetry in healthy men

• Published in: European journal of nuclear medicine and molecular imaging Vol. 41; no. 10; p. 1947
• Main Authors: Luoto, Pauliina, Suilamo, Sami, Oikonen, Vesa, Arponen, Eveliina, Helin, Semi, Herttuainen, Jukka, Hietamäki, Johanna, Holopainen, Aila, Kailajärvi, Marita, Peltonen, Juha M, Rouru, Juha, Sallinen, Jukka, Scheinin, Mika, Virta, Jere, Virtanen, Kirsi, Volanen, Iina, Roivainen, Anne, Rinne, Juha O
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer Nature B.V 01-10-2014
• Subjects: Brain; Dosimetry; Kinetics; Medical imaging; Mens health; Metabolism; Neurons; Pharmacology; Plasma; Radiation therapy
• ISSN: 1619-7070; 1619-7089
• DOI: 10.1007/s00259-014-2782-y

^sup 11^C-labelled 1-[(S)-1-(2,3-dihydrobenzo[1,2]dioxin-2-yl)methyl]-4-(3-methoxy-methylpyridin-2-yl)-piperazine (^sup 11^C-ORM-13070) is a novel PET tracer for imaging of [alpha]^sub 2C^-adrenoceptors in the human brain. Brain [alpha]^sub 2C^-adrenoceptors may be therapeutic targets in several neuropsychiatric disorders, including depression, schizophrenia and Alzheimer's disease. To validate the use of ^sup 11^C-ORM-13070 in humans, we investigated its radiometabolism, pharmacokinetics, whole-body distribution and radiation dose. Radiometabolism was studied in a test-retest setting in six healthy men. After intravenous injection of ^sup 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 ^sup 11^C-ORM-13070 and radiation exposure were investigated by dynamic PET/CT imaging without blood sampling. Two radioactive metabolites of ^sup 11^C-ORM-13070 were detected in human arterial plasma. The proportion of unchanged ^sup 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 ^sup 11^C-ORM-13070 in arterial plasma were 0.0117±0.0056 min^sup -1^ and 73.6±35.8 min, respectively. The organs with the highest absorbed doses were the liver (12 [mu]Sv/MBq), gallbladder wall (12 [mu]Sv/MBq) and pancreas (9.1 [mu]Sv/MBq). The mean effective dose was 3.9 [mu]Sv/MBq, with a range of 3.6 - 4.2 [mu]Sv/MBq. ^sup 11^C-ORM-13070 was rapidly metabolized in human subjects after intravenous injection. The effective radiation dose of ^sup 11^C-ORM-13070 was in the same range as that of other ^sup 11^C-labelled brain receptor tracers. An injection of 500 MBq of ^sup 11^C-ORM-13070 would expose a subject to 2.0 mSv of radiation. This supports the use of ^sup 11^C-ORM-13070 in repeated PET scans, for example, in receptor occupancy trials with novel drug candidates.[PUBLICATION ABSTRACT]