In Vitro Ligand Binding Kinetics Explains the Pharmacokinetics of [¹⁸F]FE-PE2I in Dopamine Transporter PET Imaging

Abstract

Two of the most popular positron emission tomography (PET) tracers, [ 11 C]PE2I and [ 18 F]FE-PE2I, used to quantify dopamine transporters (DAT), display dissimilar kinetic behavior in in vivo assays. This difference can be explained by comparing values of kinetic rate constants, which characterize interaction of these tracers with DAT sites in vitro. At the same time, this kinetic analysis showed that the overall binding mechanism is similar for these two tracers and includes a fast step of complex formation followed by a slow isomerization step of this complex. Comparison with previous PE2I data revealed that isomerization of the DAT complex with PE2I occurs three times faster than in the case of FE-PE2I, which leads to the slower onset of peak specific binding of the former tracer in the DAT-rich regions. Therefore, ligands with slower isomerization on-rate, including [ 18 F]FE-PE2I, seem to be better tracers in vivo, and their properties can be predicted in vitro.

[18F]FE-PE2I PET is a feasible alternative to [123I]FP-CIT SPECT for dopamine transporter imaging in clinically uncertain parkinsonism

“…[ 18 F]FE-PE2I binding is unaffected by anti-Parkinsonian drugs in rats [ 11 ] and a dopamine transporter blocking study with Modafinil supports the use of [ 18 F]FE-PE2I as a selective dopamine transporter marker [ 12 ]. Labelling with 11 C shows slow and less favourable kinetics [ 13 – 15 ]. In 2012, [ 18 F]FE-PE2I showed promising results in 10 healthy subjects [ 16 ] and this was substantiated by Shingai and co-workers [ 17 ] who found an age-related decline in DAT density of approximately 7.5% per decade in the caudate and putamen and 3.4% in substantia nigra.…”

A multicompartment model for intratumor tissue‐specific analysis of DCE‐MRI using non‐negative matrix factorization

“…In some recent PET studies, the pharmacokinetic parameters of the injected tracers were also used to evaluate the pharmacokinetic properties and study the tumors and intratumor heterogeneity. 44 This indicates that the kinetic parameters characterizing the intratumor interaction in vivo can completely model the pharmacodynamic behavior of PET tracers in vivo. Therefore, an estimation of the kinetic parameters can be a promising future for PET studies, and our algorithm does not limit certain data types, which means it can also be a useful tool for an estimation in PET.…”

“…In some recent PET studies, the pharmacokinetic parameters of the injected tracers were also used to evaluate the pharmacokinetic properties and study the tumors and intratumor heterogeneity 44 . This indicates that the kinetic parameters characterizing the intratumor interaction in vivo can completely model the pharmacodynamic behavior of PET tracers in vivo .…”

Longitudinal DAT changes measured with [18F]FE-PE2I PET in patients with Parkinson’s disease; a validation study

“…Due to the longer half-life of 18 F vs 11 C, [ 18 F]FE-PE2I can be distributed also to centres that do not have a radioligand-production facility. Furthermore, the fast kinetic properties of [ 18 F]FE-PE2I and the low production of blood–brain barrier crossing radiometabolites are also advantages in terms of quantification ( Fazio et al, 2015 , Kukk et al, 2018 , Morbelli et al, 2020 , Sasaki et al, 2012 , Varrone et al, 2009 , Varrone et al, 2011 ).…”