Quantification of [11C]ORM-13070 PET

[C-11]ORM-13070

[11C]ORM-13070 is a selective antagonist radioligand for the α2C adrenoceptor subtype (Arponen et al., 2010, 2010b, and 2014). In the brain, the highest densities of α2C adrenoceptors (α2C-AR, ADRA2C) are found in the ventral and dorsal striatum, and the distribution is well conserved between rodents and humans (Scheinin et al., 1994; Holmberg et al., 2003; Fagerholm et al., 2008). Significant proportion of α2C-ARs are located intracellularly in Golgi compartments, and can be recycled from/to the plasma membrane, depending on agonist (noradrenaline) or other stimulation (Chotani and Flavahan, 2011; Jahnsen and Uhlén, 2013).

[11C]ORM-13070 can be produced with high molar activity, and it readily penetrates the blood-brain barrier (BBB), unlike the previously developed α2C-specific PET tracers (Arponen et al., 2014). The effective radiation dose is in the same range as that of other 11C-labelled brain receptor radiopharmaceuticals, and is thus suitable for repeated PET studies in humans (Luoto et al., 2014). [11C]ORM-13070 can be used to assess the α2C-AR density with good repeatability in the high-binding regions (Scheinin et al., 2013; Lehto et al., 2015a) and the adrenoceptor occupancy in drug development (Lehto et al., 2015b), and to detect increase in synaptic noradrenaline levels (Finnema et al., 2015; Lehto et al., 2015c and 2016).

Kinetics of [11C]ORM-13070 in the rat and mouse brain is very fast, with the peak radioactivity at about 1-2 min after tracer injection (Arponen et al., 2014). Also in human brain the peak was observed during the first 2-3 minutes (Luoto et al., 2014).

Elimination of 11C radioactivity in rodents and humans seems to happen through biliary excretion and gastrointestinal tract (Arponen et al., 2014; Luoto et al., 2014).

Input function

Radioactive metabolites of [11C]ORM-13070

Two polar radioactive metabolites were detected in rat plasma, M1 in higher fractions and M2 in low fractions (Arponen et al., 2014; Luoto et al., 2014). In the rodents, at 10 min p.i. only 1/3 of the plasma radioactivity was due to the parent tracer, but in the striatum about 90% and in cerebellar cortex about 80% was still parent tracer (Arponen et al., 2014). In humans the metabolism was somewhat slower, at 10 min almost half of the radioactivity in the plasma was still due to the parent tracer (Luoto et al., 2014). Dexmedetomidine affects the fraction of parent tracer in plasma (Lehto et al., 2016).

Radioactive metabolites could not be detected with HPLC-MS method, suggesting that both are volatile compounds with small molecular weight (Arponen et al., 2014). Thus the radioactive metabolites should not have any specific binding to α2C or other receptors. Demethylation is the main metabolic route of ORM-13070, and in case of [11C]ORM-13070 the -O-CH3 group contains the 11C label. It can be speculated that label-carrying metabolites are [11C]methanol, [11C]formaldehyde, [11C]formate or some of their further metabolic products. [11C]Formaldehyde can bind to cellular proteins, and [11C]methyl group can be incorporated in new molecules. Small polar radiometabolites can markedly decrease the signal-to-background ratio (Johansen et al., 2018).

Only M1 was observed in the brain (Arponen et al., 2014), suggesting that M1 can pass the BBB, but M2 cannot or its distribution volume in the brain is very small.

Hill type function can be fitted to the plasma fraction curves, to calculate plasma TACs of parent tracer, M1, and M2 (Luoto et al., 2014).

Plasma-to-blood ratio

M1 penetrates red blood cell (RBC) membrane, but parent radiotracer does not (possibly due to high affinity to plasma proteins), and the level of the RBC-to-plasma ratio suggests that also M2 stays in plasma (Luoto et al., 2014). [11C]formaldehyde could enter erythrocytes by passive diffusion. At physiological pH, [11C]formic acid is in its protonated form, and would mainly stay in the plasma. [11C]CO2 passively diffuses into erythrocytes, binding to haemoglobin, but [11C]HCO3- is transported across RBC membrane by Cl-HCO3 exchanger (Johansen et al., 2018).

Hill type function can be used to fit the RBC-to-plasma ratio curve (Luoto et al., 2014).

Plasma protein binding

Binding to plasma proteins decreased over time (Arponen et al., 2014), suggesting that [11C]ORM-13070 binds to plasma proteins, but its radioactive metabolites do not. In plasma of healthy humans 95% of [11C]ORM-13070 was bound to plasma proteins (Luoto et al., 2014).

Reference region

Cerebellar cortex can be used as reference region in data analysis, because it is practically devoid of α2C-AR in mice, rats, and humans (Scheinin et al., 1994; Winzer-Serhan et al., 1997; Holmberg et al., 1999 and 2003; Schambra et al., 2005; Fagerholm et al., 2008).

Ratio method

A robust index of the concentration of available receptors can be calculated as the ratio of radioactivity concentrations in the region-of-interest and reference region. The ratio minus one ("bound per free", B/F) correlates with binding potential, and can be easily calculated pixel-by-pixel to produce parametric binding maps.

In human [11C]ORM-13070 PET studies, time interval 5-30 min or 10-20 min after administration can be used for the ratio calculation (Lehto et al., 2015a, 2015b, and 2016). Using cerebellum as the reference region, the bound/free ratio during time interval of 5–30 min was largest in the dorsal striatum, and the pattern of [11C]ORM-13070 binding was in agreement with receptor density results previously derived from postmortem autoradiography (Fagerholm et al., 2008). While the B/F ratio was quite low (0.77 in the putamen and 0.58 in the caudate nucleus), the test-retest variability was still acceptable. B/F ratios were also convergent with the results obtained using compartmental models (Lehto et al., 2015a).

B/F ratios can be used to assess the occupancy of α2C-ARs and the relationship between the occupancy and the concentration of drug in plasma (Lehto et al., 2015b; Shahid et al., 2020).


See also:


Literature

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Updated at: 2022-02-13
Created at: 2014-06-24
Written by: Vesa Oikonen