Analysis of [18F]NS12137 PET data
[18F]NS12137 is a radiopharmaceutical that targets noradrenaline transporter (NAT). NAT can be used as a marker of sympathetic nervous system activity and innervation, and in the CNS degeneration of the noradrenergic system is typical in neurodegenerative diseases. As an electrostatically neutral molecule [18F]NS12137 can cross the blood-brain barrier. (Kirjavainen et al., 2018).
Numerous NAT targeting radioligands have been developed and widely used, but many of them display slow kinetics and relatively low specific-to-nonspecific uptake ratio, limiting their clinical use for detecting neurodegeneration in cortical brain regions where the NAT density is low. [11C]NS8880 was developed to solve these problems, and it indeed has faster kinetics than [11C]MeNER in pigs and rats (Vase et al., 2014). NS8880 has much higher affinity and selectivity towards NET (IC50 5 nM) than to serotonin transporters (IC50 260 nM) and dopamine transporters (IC50 2000 nM). Despite this the binding potential was not improved (Vase et al., 2014).
In preclinical studies [18F]NS12137 has been shown to be a promising radiotracer for NAT imaging in the brain (Kirjavainen et al., 2018; López-Picón et al., 2019). In rats the highest uptake was seen in locus coeruleus, which could be blocked with nisoxetine, a standard selective norepinephrine reuptake inhibitor. Peak brain uptake was reached at 4 min after administration in rats (López-Picón et al., 2019). Locus coeruleus-to-cerebellum ratio increased to ∼10, possibly reaching maximum at 3-4 hours after administration. Thalamus-to-cerebellum ratio reached its maximum (∼2) about 1 h after administration. No radioactive metabolites were seen in the brain tissue. In plasma, free 18F- and one polar radioactive metabolite was seen (Kirjavainen et al., 2018).
Human brain PET data from studies using another NAT radioligand, (S,S)-[18F]FMeNER-D2, have been analysed using two-tissue compartmental model with arterial plasma input function, and several reference tissue input models (Arakawa et al., 2008). Caudatus has been used as the reference region because of its negligible NAT density. Estimation of BPND using SRTM and MRTM leads to positive bias in regions with low NAT density, and in all brain regions when ratio method (time range 2-3 h) was used (Arakawa et al., 2008).
Kirjavainen AK, Forsback S, López-Picón FR, Marjamäki P, Takkinen J, Haaparanta-Solin M, Peters D, Solin O. 18F-labeled norepinephrine transporter tracer [18F]NS12137: radiosynthesis and preclinical evaluation. Nucl Med Biol. 2018; 56: 39-46. doi: 10.1016/j.nucmedbio.2017.10.005.
Updated at: 2022-02-06
Created at: 2021-11-30
Written by: Vesa Oikonen