Radiochemical synthesis and evaluation in nonhuman primates of 3-[¹¹C]methoxy-4-aminopyridine: a novel PET tracer for imaging potassium channels in the CNS

Abstract

Demyelination, the loss of the protecting sheath of neurons, contributes to disability in many neurological diseases. In order to fully understand its role in different diseases and to monitor treatments aiming at reversing this process, it would be valuable to have PET radiotracers that can detect and quantify molecular changes involved in demyelination such as the uncovering and upregulation of the axonal potassium channels Kv1.1 and Kv1.2. Carbon-11 labeled radiotracers present the advantage of allowing for multiple scans on the same subject in the same day. Here, we describe [11C|3MeO4AP, a novel 11C-labeled version of the K+ channel tracer [18F]3F4AP, and characterize its imaging properties in two nonhuman primates including a monkey with a focal brain injury sustained during a surgical procedure three years prior to imaging. Our findings show that [11C]3MeO4AP is brain permeable, metabolically stable and has high plasma availability. When compared with [18F]3F4AP, [11C]3MeO4AP shows very high correlation in volumes of distribution (VT) confirming a common target. [11C]3MeO4AP shows slower washout than [18F]3F4AP suggesting stronger binding. Finally, similar to [18F]3F4AP, [11C]3MeO4AP is highly sensitive to the focal brain injury. All these features make it a promising radioligand for imaging demyelinated lesions.

Radiosynthesis automation, non-human primate biodistribution and dosimetry of K+channel tracer [11C]3MeO4AP

“…The brain kinetics can also be observed in horizontal brain slices (Fig. 5), which show higher signal in grey matter than white matter as previously described [10].…”

“…The semi-automated radiosynthesis of PET tracer [ 11 C]3MeO4AP was achieved using a similar method as previously reported [10]. Starting from 10.73 GBq -16.65 GBq (290 mCi -450 mCi) of [ 11 C] CH3I, 1.37 GBq -1.89 GBq (37 mCi -51 mCi) of [ 11 C]3MeO4AP was synthesized in 11.3 ± 2.1 % (n = 4) non-decay corrected radiochemical yield and >99% of radiochemical purity in ~45 min of synthesis and purification time.…”

“…4AP binds to the potassium channels in demyelinated axons, reducing the abnormal efflux of K + ions and restoring axonal conduction [6,7]. Several 4AP based PET tracers have been developed by our group (Figure 1) [8][9][10][11]. The fluorine-18 based PET tracer [ 18 F]3-fluoro-4-aminopyridine ([ 18 F]3F4AP) has been characterized in healthy non-human primates and healthy human subjects, showing selective binding to potassium channels, high brain penetration, high metabolic stability, high plasma availability, high reproducibility, high specificity, and fast kinetics [8].…”

“…Due to their shorter half-life, carbon-11 PET tracers generally display lower effective doses and offer the opportunity to scan the same subject twice on the same day [13][14][15][16][17][18]. Several carbon-11 labeled 4AP-based PET tracers have been reported including 3-[ 11 C]trifluoromethyl-4-aminopyridine ([ 11 C]3CF34AP) [9,19], 3-[ 11 C]methoxy-4-aminopyridine ([ 11 C]3MeO4AP) [10], and 3-[ 11 C]methyl-4-aminopyridine ([ 11 C]3Me4AP) [11] (Figure 1). Among them, [ 11 C]3MeO4AP was the only one that showed marked uptake in a three-year old focal traumatic brain injury in a rhesus macaque.…”

“…Among them, [ 11 C]3MeO4AP was the only one that showed marked uptake in a three-year old focal traumatic brain injury in a rhesus macaque. Additionally, [ 11 C]3MeO4AP showed several promising properties such as high brain permeability, high metabolically stability, high plasma availability, and higher in vivo binding affinity and specificity to potassium channels compared with [ 18 F]3F4AP [10]. The properties mentioned above make [ 11 C]3MeO4AP a promising candidate for imaging demyelinating diseases.…”