Abstract
BackgroundThe β-amyloid radiotracer [11C] PiB is extensively used for the Positron Emission Tomography (PET) diagnosis of Alzheimer’s Disease and related dementias. For clinical use, [11C] PiB is produced using the 11C-methylation method ([11C] Methyl iodide or [11C] methyl triflate as 11C-methylation agents), which represents the most employed 11C-labelling strategy for the synthesis of 11C-radiopharmaceuticals. Recently, the use of direct [11C]CO2 fixation for the syntheses of 11C-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 [11C]CO2.This paper presents an optimised alternative one-pot methodology of [11C]CO2 fixation-reduction for the rapid synthesis of [11C] PiB using an automated commercial platform and its quality control.Results[11C] PiB was obtained from a (25.9 ± 13.2)% (Average ± Variation Coefficient, n = 3) (end of synthesis, decay corrected) radiochemical yield from trapped [11C]CO2 after 1 min of labelling time using PhSiH3 / 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 [11C] PiB from cyclotron-produced [11C]CO2 was (14.8 ± 12.1)%, decay corrected) and 9.88 GBq (± 6.0%), respectively. These are higher values compared to that of the 11C-methylation method with [11C]CH3OTf (~ 8.3%).ConclusionsThe viability of the system PhSiH3 / TBAF to efficiently promote the radiosynthesis of [11C] PiB via direct [11C]CO2 fixation-reduction has been demonstrated. [11C] 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.
Highlights
The aim of this work was to assess the applicability of the PhSiH3 / Tetrabutylammonium fluoride (TBAF) mediated reductive incorporation of [11C]CO2 for the radiosynthesis of the β-amyloid tracer [11C]Pittsburg compound B-6hydroxybenzothiazole) (PiB)
Tetrabutylammonium fluoride (TBAF) 1.0 M in THF and PhSiH3 (97%) were acquired from Aldrich, stored in a desiccator and handled in an inert atmosphere (N2). 6-OH-BTA-0 was obtained from Siquimia. 4-Toluidine was purchased from Fluka. 6-OH-BTA-0, 6-OH-BTA-1 and 6(MeO)-BTA-0 were used as analytical standards and were purchased from ABX (GmbH)
Optimisation of N-[11C-methyl]-4-toluidine To assess the potential of the [11C]CO2 reduction-fixation methodology with PhSiH3 / TBAF, the research began by selecting the primary aromatic amine 4-toluidine (4-methylaniline) as a model substrate
Summary
The compound 2-(4′-N-[11C]methylaminophenyl)-6-hydroxybenzothiazole, known as [11C]6-OH-BTA-1 or [11C] Pittsburg Compound B ([11C]PiB), has long been recognised as a potent PET radiotracer for beta-amyloid (Aβ) plaque imaging in the brains of patients with Alzheimer’s Disease (AD) and other forms of dementia The original radiosynthesis of [11C] PiB was performed by Mathis et al (2003). It consisted of the 11C-N-methylation of the precursor 2-(4′-aminophenyl)-6-methoxymethoxybenzothiazole (6-MOMO-BTA-0) with [11C] methyl iodide ([11C]CH3I), followed by an acidic deprotection of the methoxymethyl group. For clinical use, [11C] PiB is produced using the 11C-methylation method ([11C] Methyl iodide or [11C] methyl triflate as 11C-methylation agents), which represents the most employed 11C-labelling strategy for the synthesis of 11C-radiopharmaceuticals. This paper presents an optimised alternative one-pot methodology of [11C]CO2 fixation-reduction for the rapid synthesis of [11C] PiB using an automated commercial platform and its quality control
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