Fully automated synthesis of [18F]T807, a PET tau tracer for Alzheimer’s disease

Abstract

Abstract-The authentic standard T807 and its nitro-precursor T807P as well as t-Boc-protected T807P precursor for radiolabeling were synthesized from (4-bromophenyl)boronic acid, 3-bromo-4-nitropyridine and 3-bromo-6-nitropyridine with overall chemical yield 27% in three steps, 4-7% in three to five steps, and 3-8% in four to five steps, respectively.

An updated radiosynthesis of [18F]AV1451 for tau PET imaging

“…Issues with solubility of the nitro-precursor have been partially resolved by N-Boc protection of the carbazole nitrogen, which improves solubility by increasing the lipophilicity of the molecule. Literature reports are unclear as to whether N-Boc protection improves radiochemical conversion or if increased yields are due to the solubility afforded (Shoup et al 2013 ; Gao et al 2015 ). Ambiguity also surrounds the deprotection of N-Boc-protected [ 18 F]AV1451 in the literature: Shoup and Gao describe the N-Boc group being removed concomitantly with fluorination through either thermal promotion or due to the basic reaction conditions (Shoup et al 2013 ; Gao et al 2015 ), while Holt and co-workers add HCl following fluorination to deprotect in a separate deprotection step (Holt et al 2016 ).…”

“…Reflecting its widespread use, several different syntheses of [ 18 F]AV1451 suitable for clinical use have been reported. Shoup and Gao both reported syntheses of [ 18 F]AV1451 from N-Boc-protected nitro precursor (Shoup et al 2013 ; Gao et al 2015 ), which eliminated the need for the reduction of the nitro precursor prior to purification that the original report required to facilitate purification of [ 18 F]AV1451 (Xia et al 2013 ). More recently, Holt et al reported 18 F-fluorination of N-Boc-protected trimethylammonium precursor by microwave irradiation (Holt et al 2016 ).…”

“…While these reported synthesis of [ 18 F]AV1451 represented an attractive starting point, we were unsatisfied with various aspects of these reports, including: i) ambiguity surrounding deprotection of Boc-protected [ 18 F]AV1451, since both Shoup and Gao describe the Boc group being removed concomitantly with fluorination (through either thermal promotion or due to the basic reaction conditions) while Holt includes a separate acid-mediated deprotection (Shoup et al 2013 ; Gao et al 2015 ; Holt et al 2016 ); ii) the need for solid-phase extraction (SPE) purification steps both pre- and post-semi-preparative HPLC purification, which necessitates a reconfiguration of the synthesis module in the Shoup method; iii) the Gao method used a purpose built set-up which could complicate compliance with current Good Manufacturing Practice (cGMP), and the literature report contained none of the quality control and release data required to determine if the procedure was compliant with the US Pharmacopeia; and iv) the use of an MeCN-containing mobile phase in the Gao method (our laboratory has made applying green methods when possible a priority to reduce environmental impact and risk associated with class 2 solvents such as MeCN (Stewart et al 2015 ), and simplify quality control (QC) testing since eliminating such solvents reduces residual solvent analysis to an annual QC test). To address these issues, we have undertaken a detailed investigation of the radiosynthesis of [ 18 F]AV1451, and herein report insights into the N -Boc deprotection and a new operationally simple, greener method for the radiosynthesis and purification of the radiotracer that uses a commercial synthesis module without reconfiguration, and does not utilize any class 2 solvents in the synthesis or purification.…”

“In‐loop” 18F‐fluorination: A proof‐of‐concept study

“…This “in‐loop” [ 18 F]fluorination methodology was then applied for the syntheses of [ 18 F]T807 and [ 18 F]FEPPA (Table ). The synthesis of [ 18 F]T807 has previously been reported by several research groups in RCYs ranging from 14% to 32%. [ 18 F]T807 is commonly produced via our two‐step one‐pot procedure, which entails firstly the nucleophilic 18 F‐fluorination of the nitro‐ or tetramethylammonium‐based precursor compound, followed by thermal Boc deprotection to form the desired product.…”

Extracellular Tau Oligomers Induce Disruption of Endogenous Tau Distribution, Invasion of Tau into the Somatodendritic Compartment and Axonal Transport Dysfunction

“…The most notable of these is Pittsburgh compound B which binds deposits of Ab, allowing for PET imaging of pathology in living individuals [29]. Several PET tracers are also in development for tau imaging [30][31][32][33]. Levels of total tau and Ab in the CSF show alteration early in their disease course (increasing and decreasing respectively) [34] and certain tau phosphoepitopes (Thr181 and Thr213) [35][36][37][38] in the CSF may be indicative of disease, although these tests require a lumbar puncture.…”