A concise radiosynthesis of the tau radiopharmaceutical, [¹⁸F]T807

Abstract

Fluorine-18 labelled 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole ([18F]T807) is a potent and selective agent for imaging paired helical filaments of tau (PHF-tau) and is among the most promising PET radiopharmaceuticals for this target in early clinical trials. The present study reports a simplified one-step method for the synthesis of [18F]T807 that is broadly applicable for routine clinical production using a GE Tracerlab™ FXFN radiosynthesis module. Key facets of our optimized radiosynthesis include development and use of a more soluble protected precursor, tert-butyl 7-(6-nitropyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate, as well as new HPLC separation conditions that enable a facile one-step synthesis. During the nucleophilic fluorinating reaction with potassium cryptand [18F]fluoride (K[18F]/K222) in DMSO at 130 °C over 10 min, the precursor is concurrently deprotected. Formulated [18F]T807 was prepared in an uncorrected radiochemical yield of 14 ± 3%, with a specific activity of 216 ± 60 GBq/μmol (5837 ± 1621 mCi/μmol) at the end of synthesis (60 min; n = 3) and validated for human use. This methodology offers the advantage of faster synthesis in fewer steps, with simpler automation which we anticipate will facilitate widespread clinical use of [18F]T807.

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

“…(ii) Pd(Ph3P)4, Cs2CO3, 1,4-dioxane, reflux; 5 (10-16%) and 6 (15-32% 12,13,16,18 It is difficult to directly purify labeled product [ 18 F]T807 from unlabeled precursor T807P by a semi-preparative reverse-phase (RP) high performance liquid chromatography (HPLC) due to their close polarity. Therefore, the reduction of -NO 2 to -NH 2 is needed after F-18 labeling step.…”

“…[20][21][22][23][24] However, the solubility of T807P in DMSO is not very high, and thus F-18 labeling yield was low. 18 To reduce excess amount of the unreacted precursor T807P (1 mg) to amino-T807, huge amount of Fe powder (90-100 mg) need to be used, thus it is not easy to perform routine automation, and instead manual synthesis is required. The overall synthesis, purification and formulation time was ~90 min from end of bombardment (EOB 18 The overall synthesis, purification and formulation time was 60-70 min from EOB.…”

“…18 To reduce excess amount of the unreacted precursor T807P (1 mg) to amino-T807, huge amount of Fe powder (90-100 mg) need to be used, thus it is not easy to perform routine automation, and instead manual synthesis is required. The overall synthesis, purification and formulation time was ~90 min from end of bombardment (EOB 18 The overall synthesis, purification and formulation time was 60-70 min from EOB. t-Boc-protected T807P has made more easily amenable for routine automation with relatively short radiosynthesis time and much higher radiochemical yield.…”

“…Our study has proved that the maximum in-target SA for our [ 18 F]-tracers is ~370 GBq/mol at EOB produced in our cyclotron (Siemens RDS-111 Eclipse) and home-built automated [ 18 F]-radiosynthesis unit. The SA for our [ 18 F]-tracers usually ranges from 37 to 370 GBq/mol at EOB according to our previous works for the [ 18 Furthermore, in order to make more product radioactivity, we also modified the published semipreparative HPLC conditions 12,13,18 including column, mobile phase and flow rate to shorten the retention time of [ 18 F]T807. Although this modification helped to shorten the overall production time, it potentially could bring the organic solvent residue issue (CH 3 CN from mobile phase) since CH 3 CN residue has limit restriction for clinical usage.…”

“…The published and patented synthesis of the authentic standard T807 and target tracer [ 18 F]T807 lacks synthetic detail, and the key steps gave poor yield and was difficult to reproduce in our hands. Therefore, we revisited the reported literature methods 12,13,17,18 and investigated alternate approaches and modifications that eventually resulted in a high-yield synthesis of T807 and […”