Synthesis of a PET tau tracer [11C]PBB3 for imaging of Alzheimer’s disease

Abstract

Abstract-The authentic standard PBB3 and its precursor N-desmethyl-PBB3 as well as TBS-protected N-desmethyl-PBB3 precursor for radiolabeling were synthesized from 5-bromo-2-nitropyridine, acrolein diethyl acetal, 6-methoxy-2-methylbenzothiazole, and diethylchlorophosphate with overall chemical yield 1% in six steps, 2% in five steps, and 1% in six steps, respectively. [11 C]PBB3 was prepared from either desmethyl-PBB3 or TBS-protected desmethyl-PBB3 with [11 C]CH 3 OTf through N-[ 11 C]methylation and isolated by HPLC combined with SPE in 20-25% and 15-20% radiochemical yield, respectively, based on [ 11 C]CO 2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity at EOB was 370-1110 GBq/mol with a total synthesis time of ~40-minutes from EOB.

Synthesis of carbon-11-labeled isonicotinamides as new potential PET agents for imaging of GSK-3 enzyme in Alzheimer’s disease

“…The factors that affect the EOB SA significantly to lead to such a wide range from 370 to 1110 GBq/mol are mainly from two parts: (1) carrier from the [ 11 C]-target, and (2) carrier from the [ 11 C]radiosynthesis unit. 36,37 We have optimized the [ 11 C] gas irradiation target system and the [ 11 C]-radiosynthesis unit to eliminate 12 C carrier-added as much as possible and to reach the high end of the SA. To help produce high SA [ 11 C]CO 2 , we usually do 10-minute target preburn for 2-3 times, with the same beam current, prior to the actual production run.…”

Synthesis of carbon-11-labeled CK1 inhibitors as new potential PET radiotracers for imaging of Alzheimer’s disease

“…The factors that affect the EOB MA significantly to lead to such a wide range have been discussed in our previous works. [34][35][36] The general methods to increase SA have been described as well, and the SA of our [ 11 C]-tracers is significantly improved. [34][35][36] The 'wide range' of MA we reported is for the same [ 11 C]-tracer produced in different days, because very different [ 11 C]-target and [ 11 C]-radiosynthesis unit situations would make MA in a wide range.…”

“…[34][35][36] The general methods to increase SA have been described as well, and the SA of our [ 11 C]-tracers is significantly improved. [34][35][36] The 'wide range' of MA we reported is for the same [ 11 C]-tracer produced in different days, because very different [ 11 C]-target and [ 11 C]-radiosynthesis unit situations would make MA in a wide range. For a [ 11 C]-tracer produced in the same day, the MA of the same tracer in different production runs will be in a small range, because [ 11 C]-target and [ 11 C]-radiosynthesis unit would not be much different in the same day.…”

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

“…Tau is found in the CNS in six alternatively spliced isoforms, and interestingly, the isoform composition of tau aggregates varies among different tauopathies, such as corticobasal degeneration (predominantly 4R) [31], Pick's Disease (predominantly 3R) [32], and AD (approximately equal amounts of 3R and 4R [33]). Moreover, intronic mutations resulting in the alteration of tau isoform ratios, but not protein levels, can be fully penetrant for neurological disorders, indicating that isoforms play an important role in tau pathology [56].…”

“…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.…”