Improved synthesis of SV2A targeting radiotracer [11C]UCB-J

Abstract

Introduction[11C]UCB-J is a tracer developed for PET (positron emission tomography) that has high affinity towards synaptic vesicle glycoprotein 2A (SV2A), a protein believed to participate in the regulation of neurotransmitter release in neurons and endocrine cells. The localisation of SV2A in the synaptic terminals makes it a viable target for in vivo imaging of synaptic density in the brain. Several SV2A targeting compounds have been evaluated as PET tracers, including [11C]UCB-J, with the aim to facilitate studies of synaptic density in neurological diseases.The original two-step synthesis method failed in our hands to produce sufficient amounts of [11C]UCB-J, but served as an excellent starting point for further optimizations towards a high yielding and simplified one-step method. [11C]Methyl iodide was trapped in a clear THF-water solution containing the trifluoroborate substituted precursor, potassium carbonate and palladium complex. The resulting reaction mixture was heated at 70 °C for 4 min to produce [11C]UCB-J.ResultsAfter semi-preparative HPLC purification and reformulation in 10% ethanol/phosphate buffered saline, the product was obtained in 39 ± 5% radiochemical yield based on [11C]methyl iodide, corresponding to 1.8 ± 0.5 GBq at EOS. The radiochemical purity was > 99% and the molar activity was 390 ± 180 GBq/μmol at EOS. The product solution contained < 2 ppb palladium.ConclusionsA robust and high yielding production method has been developed for [11C]UCB-J, suitable for both preclinical and clinical PET applications.

Automated radiosynthesis of [11C]UCB‐J for imaging synaptic density by positron emission tomography

“…The radiosynthesis of [ 11 C]UCB-J is based on the application of the palladium(0)-mediated Suzuki cross-coupling reaction between the carbon-11 methyliodide ([ 11 C]CH 3 I) and trifluoroborate precursor 3 (Figure 1). 7,10,11,13,14 Initially explored method employed a more common Suzuki reacting partner, ie, the corresponding boronic acid 15 (eg, 4 in Scheme 1) as a radiolabelling precursor; however, the boronic acid precursor 4 proved to be unstable upon storage resulting in poor reproducibility and unreliable radiochemical yields. Further investigation indicated that while trifluoroborate 3 can be used as a radiolabelling precursor for [ 11 C]UCB-J, the actual reacting specie is the boronic acid, thus necessitating a need for a mixture of trifluoroborate 3 and 3-10% of the boronic acid 4 to be present in the reaction vessel.…”

“…The radiosynthesis of [ 11 C]UCB‐J is based on the application of the palladium(0)‐mediated Suzuki cross‐coupling reaction between the carbon‐11 methyliodide ([ 11 C]CH 3 I) and trifluoroborate precursor 3 (Figure ) . Initially explored method employed a more common Suzuki reacting partner, ie, the corresponding boronic acid (eg, 4 in Scheme ) as a radiolabelling precursor; however, the boronic acid precursor 4 proved to be unstable upon storage resulting in poor reproducibility and unreliable radiochemical yields.…”

A comparative study on Suzuki‐type 11C‐methylation of aromatic organoboranes performed in two reaction media

“…Analysis of residual palladium in the isolated product was not performed but it can be noted that our previous studies have only showed extremely low amounts. 5,19 The Suzuki-type coupling reaction with [ 11 C]methyl iodide is a multistep process where a 11 C-methyl palladium complex is formed by oxidative addition, the complex reacts with the organoborane precursor in a transmetalation step and finally the 11 C-labeled product is released by reductive elimination (Figure 2A). 18,20,21 The organoborane compound enters in transmetallic step in the form of a boronic acid.…”

The Synaptic Vesicle Protein 2A Interacts With Key Pathogenic Factors in Alzheimer’s Disease: Implications for Treatment

“…However, the specific molecular mechanisms leading to compromised synaptic function remains unclear. Synaptic vesicle glycoprotein 2A (SV2A), an essential vesicle membrane protein ubiquitously expressed in synapses, could serve as a suitable biomarker for synaptic density ( Madeo et al, 2014 ; Nicolas et al, 2016 ; Stockburger et al, 2016 ; Tokudome et al, 2016 ; Chen et al, 2018 ; Rokka et al, 2019 ). SV2A is also involved in synaptic vesicle transport, exocytosis, neurotransmitter release, and regulates gene and protein expression ( Cohen et al, 2011 ; Mendoza-Torreblanca et al, 2013 ).…”