Evaluation of the potassium channel tracer [¹⁸F]3F4AP in rhesus macaques

Abstract

Demyelination causes slowed or failed neuronal conduction and is a driver of disability in multiple sclerosis and other neurological diseases. Currently, the gold standard for imaging demyelination is MRI, but despite its high spatial resolution and sensitivity to demyelinated lesions, it remains challenging to obtain specific and quantitative measures of demyelination. To understand the contribution of demyelination in different diseases and to assess the efficacy of myelin-repair therapies, it is critical to develop new in vivo imaging tools sensitive to changes induced by demyelination. Upon demyelination, axonal K + channels, normally located underneath the myelin sheath, become exposed and increase in expression, causing impaired conduction. Here, we investigate the properties of the K + channel PET tracer [ 18 F]3F4AP in primates and its sensitivity to a focal brain injury that occurred three years prior to imaging. [ 18 F]3F4AP exhibited favorable properties for brain imaging including high brain penetration, high metabolic stability, high plasma availability, high reproducibility, high specificity, and fast kinetics.[ 18 F]3F4AP showed preferential binding in areas of low myelin content as well as in the previously injured area.Sensitivity of [ 18 F]3F4AP for the focal brain injury was higher than [ 18 F]FDG, [ 11 C]PiB and [ 11 C]PBR28, and compared favorably to currently used MRI methods.

Radiochemical Synthesis and Evaluation of 3-[11C]Methyl-4-aminopyridine in Rodents and Non-Human Primates for Imaging Potassium Channels in the CNS

“…2C ). This increase in brain uptake upon coinjection of cold tracer is consistent with previous reports describing that high doses of 4AP analogs cause more channels to transition to the open (bindable) conformation and thus result in higher receptor binding 14, 25 .…”

“…One more aspect worth noting is that one of the monkeys used in these studies (M2) had a minor focal lesion in the brain. This lesion could be easily visualized and quantified with [ 18 F]3F4AP and [ 11 C]3MeO4AP and displayed a higher V T value and lower K 1 value than the contralateral control region 14, 29 . With [ 11 C]3Me4AP, this lesion was not visible on the PET images.…”

“…Further evaluation of [ 18 F]3F4AP in non-human primates (NHPs) showed that [ 18 F]3F4AP has excellent properties for primate brain imaging, such as high brain penetration, fast kinetics, and high metabolic stability. Furthermore, [ 18 F]3F4AP was very sensitive to a focal brain injury in a monkey 14 . More recently, due to the advantages of having short-lived radiotracers, such as allowing multiple scans on the same subject on the same day, we explored 3-[ 11 C]trifluoromethyl-4-aminopyridine ([ 11 C]3CF 3 4AP) 15 and 3-[ 11 C]methoxy-4-aminopyridine ([ 11 C]3MeO4AP) 16 as viable 11 C-labeled alternatives.…”

A comprehensive macaque fMRI pipeline and hierarchical atlas

“…The NMT is a high-resolution template generated through iterative nonlinear alignment of 31 adult rhesus macaques; it was designed for group analyses and to facilitate collaboration and replicability in macaque research. The NMT has been used as a standardized space for a multitude of macaque imaging studies ( Ainsworth et al, 2020 ; Arcaro et al, 2019 ; Ball and Seal, 2019 ; Bridge et al, 2019 , 2018 ; Guehl et al, 2020 ; Menon et al, 2019 ; Milham et al, 2018 ; Ortiz-Rios et al, 2018 ; Seidlitz et al, 2018b ), and it serves as a standardized macaque space in which data can be aligned, displayed and analyzed within Neurovault ( Gorgolewski et al, 2015 ), AFNI Cox (1996) and CIVET ( Lepage et al, this issue ).…”

A comprehensive macaque fMRI pipeline and hierarchical atlas

“…The NMT is a high-resolution template generated through iterative nonlinear alignment of 31 adult rhesus macaques; it was designed for group analyses and to facilitate collaboration and replicability in macaque research. The NMT has been used as a standardized space for a multitude of macaque imaging studies (Ainsworth et al, 2020;Arcaro et al, 2019;Ball and Seal, 2019;Bridge et al, 2019Bridge et al, , 2018Guehl et al, 2020;Menon et al, 2019;Milham et al, 2018;Ortiz-Rios et al, 2018;Seidlitz et al, 2018), and it serves as a standardized macaque space in which data can be aligned, displayed and analyzed within Neurovault (Gorgolewski et al, 2015), AFNI (Cox, 1996) and CIVET (Lepage et al, this issue).…”