¹¹C-ORM-13070, a Novel PET Ligand for Brain α₂C-adrenoceptors: Radiometabolism, Plasma Pharmacokinetics, Whole-body Distribution and Radiation Dosimetry in Healthy Men

Overview

Journal Eur J Nucl Med Mol Imaging

Specialties Biophysics
Nuclear Medicine
Radiology

Date 2014 May 20

PMID 24838249

Citations 13

Authors

Pauliina Luoto

Sami Suilamo

Vesa Oikonen

Eveliina Arponen

Semi Helin

Jukka Herttuainen

Johanna Hietamaki

Aila Holopainen

Marita Kailajarvi

Juha M Peltonen

Juha Rouru

Jukka Sallinen

Mika Scheinin

Jere Virta

Kirsi Virtanen

Iina Volanen

Anne Roivainen

Juha O Rinne

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Preclinical and evaluation of [C]ORM-13070 as PET ligand for alpha-2C adrenergic receptor occupancy using PET imaging in non-human primates.

Piel I, Constantinescu C, de la Puente Bethencourt D, Bonsall D, Rabiner E, Zasadny K J Cereb Blood Flow Metab. 2024; :271678X241291949.

PMID: 39479946 PMC: 11563544. DOI: 10.1177/0271678X241291949.

Application of the PET ligand [C]ORM-13070 to examine receptor occupancy by the α-adrenoceptor antagonist ORM-12741: translational validation of target engagement in rat and human brain.

Shahid M, Rinne J, Scheinin M, Virta J, Marjamaki P, Solin O EJNMMI Res. 2020; 10(1):152.

PMID: 33296042 PMC: 7726058. DOI: 10.1186/s13550-020-00741-y.

PET Radiotracers for CNS-Adrenergic Receptors: Developments and Perspectives.

Alluri S, Kim S, Volkow N, Kil K Molecules. 2020; 25(17).

PMID: 32899124 PMC: 7504810. DOI: 10.3390/molecules25174017.

Less Exploited GPCRs in Precision Medicine: Targets for Molecular Imaging and Theranostics.

Machado J, Silva R, Melo R, Correia J Molecules. 2018; 24(1).

PMID: 30583594 PMC: 6337414. DOI: 10.3390/molecules24010049.

Selective adrenergic alpha2C receptor antagonist ameliorates acute phencyclidine-induced schizophrenia-like social interaction deficits in rats.

Savolainen K, Ihalainen J, Jalkanen A, Forsberg M Psychopharmacology (Berl). 2018; 236(4):1245-1253.

PMID: 30535904 PMC: 6591184. DOI: 10.1007/s00213-018-5130-2.

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