Preclinical evaluation of [18F]SYN2, a novel radiotracer for myocardial perfusion imaging in PET
Authors: Krajewski S , Steczek L , Gotowicz K , Karczmarczyk U , Towpik J , Wlostowska J , Witkowska-Patena E , Kozanecki P , Dziuk M , Knuuti J , Garnuszek P , Kozanecki C 
Published: June 2024

Background/Introduction

Positron emission tomography (PET) is now an established method for myocardial perfusion imaging (MPI). The available tracers show a number of limitations, therefore the 18F-labelled tracer is in high demand now.

Purpose

The preclinical studies aimed to characterise [18F]SYN2 (18F acridinium derivative) on animal model to prove it can be used as a novel MPI radiotracer for PET.

Methods

The preclinical evaluation was conducted on Wistar rats. The utility of [18F]SYN2 as heart-targeted tracer was tested by 45-min dynamic microPET imaging. The physiological distribution and pharmacokinetics were examined on ex vivo tissue/organs radioactivity measurement at 0.25, 0.5, 1, 2, 3 and 6 h. The obtained data was extrapolated to humans using the simplest allometric scaling model. The effective dose was calculated using OLINDA/EXM® software. The pharmacokinetics in plasma (at 4, 15, 30, 60 min, 4, and 24 h) and potential toxicity studies (at 24 hour and 14 day) were evaluated after a bolus i.v. administration of 2 mg/kg of SYN2 (the non-radioactive standard). The pharmacodynamics was assessed in vitro in radioligand binding assays for 68 targets. The tracer metabolism was studied by the SYN2 incubation in rat, dog and human hepatocytes for 60 min. All animal procedures were conducted according to the European and National Legislation.

Results

The microPET images showed rapid, high and stable myocardial [18F]SYN2 uptake with an average standardized uptake value of 3.8. The biodistribution studies confirmed that [18F]SYN2 uptake in the cardiac muscle was high and stable (3.02 %ID/g at 15 min and 2.79 %ID/g at 6 h). The uptake in the liver was relatively low (max. 0.89 %ID/g at 15 min), while in the lungs was much higher and decreased rapidly over time (from 3.04 %ID/g at 15 min to 0.55 %ID/g at 6 h). The study showed that the radiotracer was eliminated predominantly by biliary excretion. The estimated effective dose for human was 0.0109 mSv/MBq. SYN2 showed rapid plasma clearance within 1 hour post injection (2.59 L/h/kg) with elimination half-life of 0.26 h. The tested dose level of 2 mg/kg was considered to be the No Observed Adverse Effect Level (NOAEL). Radioligand binding assays showed significant responses in 3/68 assays: muscarinic acetylcholine M1 and M2 receptors and potassium channel hERG. The compound was mostly metabolised via an oxidative N-dealkylation, while the fluor substituent was not separated from the molecule.

Conclusion

[18F]SYN2 showed favourable pharmacokinetic and pharmacodynamic profile in the rat model. The tracer, with its rapid plasma clearance, high and stable uptake in the myocardium allowed clear visualization of the heart in microPET. [18F]SYN2 was well-tolerated and showed moderate radiation exposure. Encouraging results of preclinical evaluation merit further exploration in clinical studies.MicroPET images of [18F]SYN2