Fully-automated radiosynthesis of the amyloid tracer [11C] PiB via direct [11C]CO2 fixation-reduction

Abstract

Background The β-amyloid radiotracer [ 11 C] PiB is extensively used for the Positron Emission Tomography (PET) diagnosis of Alzheimer’s Disease and related dementias. For clinical use, [ 11 C] PiB is produced using the 11 C-methylation method ([ 11 C] Methyl iodide or [ 11 C] methyl triflate as 11 C-methylation agents), which represents the most employed 11 C-labelling strategy for the synthesis of 11 C-radiopharmaceuticals. Recently, the use of direct [ 11 C]CO 2 fixation for the syntheses of 11 C-tracers has gained interest in the radiochemical community due to its importance in terms of radiochemical versatility and for permitting the direct employment of the cyclotron-produced precursor [ 11 C]CO 2 . This paper presents an optimised alternative one-pot methodology of [ 11 C]CO 2 fixation-reduction for the rapid synthesis of [ 11 C] PiB using an automated commercial platform and its quality control. Results [ 11 C] PiB was obtained from a (25.9 ± 13.2)% (Average ± Variation Coefficient, n = 3) (end of synthesis, decay corrected) radiochemical yield from trapped [ 11 C]CO 2 after 1 min of labelling time using PhSiH 3 / TBAF as the fixation-reduction system in Diglyme at 150 °C. The radiochemical purity was higher than 95% in all cases, and the molar activity was (61.4 ± 1.6) GBq/μmol. The radiochemical yield and activity (EOS) of formulated [ 11 C] PiB from cyclotron-produced [ 11 C]CO 2 was (14.8 ± 12.1)%, decay corrected) and 9.88 GBq (± 6.0%), respectively. These are higher values compared to that of the 11 C-methylation method with [ 11 C]CH 3 OTf (~ 8.3%). Conclusions The viability of the system PhSiH 3 / TBAF to efficiently promote the radiosynthesis of [ 11 C] PiB via direct [ 11 C]CO 2 fixation-reduction has been demonstrated. [ 11 C] PiB was obtained through a fully automated radiosynthesis with a satisfactory yield, purity and molar activity. According to the results, the one-pot methodology employed could reliably yield sufficiently high tracer amounts for preclinical and clinical use. Electronic supplementary material The online versio...

Silicon compounds in carbon-11 radiochemistry: present use and future perspectives

“…For example, the hydrosilylation of CO 2 have been used for the synthesis of a larger number of chemical structures (formamides, aldehydes, aminals) [10][11][12][13] whereas in 11 C-chemistry it's been used only for the production of 11 C-N-methylamines. 43,44 Another potential route for widening the use of 11 C-Si chemistry would be taking inspiration from the more established 11 C-boron chemistry. 60 Boron and silicon share many similarities with respect to bond energy and general chemical properties, 61,62 suggesting that they may also have similar…”

“…43 A simpler set up that would not require the use of unstable NHCs was lately proposed for the synthesis of 11 C-N-methylamines. 44 Inspired by non-radioactive experiments, 45 the radiolabelling step required the use of only hydrosilane and TBAF as fluoride source. 44 The hydrosilane and the fluoride source were initially mixed in order to form an activated pentavalent fluorosilyl anion (11, Scheme 6) which instantly reduced the delivered [ 11 C]CO 2 to [ 11 C]formate, allowing the formation of a 11 C-silylformate ([ 11 C]12, Scheme 6).…”

“…The 11 C-formyl group was then attached to the aminic precursor, yielding a 11 Cformamide that was reduced to 11 C-N-methylamine by the excess of fluorosilyl anion previously formed (Scheme 6). 44 Si Ph 44…”

“… 44 Inspired by non-radioactive experiments, 45 the radiolabelling step required the use of only hydrosilane and TBAF as fluoride source. 44 The hydrosilane and the fluoride source were initially mixed in order to form an activated pentavalent fluorosilyl anion ( 11 , Scheme 6 ) which instantly reduced the delivered [ 11 C]CO 2 to [ 11 C]formate, allowing the formation of a 11 C-silylformate ([ 11 C] 12 , Scheme 6 ). The 11 C-formyl group was then attached to the aminic precursor, yielding a 11 C-formamide that was reduced to 11 C- N -methylamine by the excess of fluorosilyl anion previously formed ( Scheme 6 ).…”

“…This fluoride-activated radiosynthesis of 11 C- N -methylamines was also fully automated and exploited for the synthesis of [ 11 C]PiB with RCY of 15% (isolated, decay-corrected) and A m 61 GBq per μmol within 32 min from EOB. 44 …”