Automated Optimized Synthesis of [18F]FLT Using Non-Basic Phase-Transfer Catalyst with Reduced Precursor Amount

Abstract

3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT) is a positron emission tomography (PET) tracer useful for tumor proliferation assessment for a number of cancers, particularly in the cases of brain, lung, and breast tumors. At present [18F], FLT is commonly prepared by means of the nucleophilic radiofluorination of 3-N-Boc-5′-O-DMT-3′-O-nosyl thymidine precursor in the presence of a phase-transfer catalyst, followed by an acidic hydrolysis. To achieve high radiochemical yield, relatively large amounts of precursor (20–40 mg) are commonly used, leading to difficulties during purification steps, especially if a solid-phase extraction (SPE) approach is attempted. The present study describes an efficient method for [18F]FLT synthesis, employing tetrabutyl ammonium tosylate as a non-basic phase-transfer catalyst, with a greatly reduced amount of precursor employed. With a reduction of the precursor amount contributing to lower amounts of synthesis by-products in the reaction mixture, an SPE purification procedure using only two commercially available cartridges—OASIS HLB 6cc and Sep-Pak Alumina N Plus Light—has been developed for use on the GE TRACERlab FX N Pro synthesis module. [18F]FLT was obtained in radiochemical yield of 16 ± 2% (decay-corrected) and radiochemical purity >99% with synthesis time not exceeding 55 min. The product was formulated in 16 mL of normal saline with 5% ethanol (v/v). The amounts of chemical impurities and residual solvents were within the limits established by European Pharmacopoeia. The procedure described compares favorably with previously reported methods due to simplified automation, cheaper and more accessible consumables, and a significant reduction in the consumption of an expensive precursor.

A Molecular Toolbox of Positron Emission Tomography Tracers for General Anesthesia Mechanism Research

“…327 Another radiotracer, [ 18 F]61, can be prepared by first labeling a precursor with 18 F and then deprotecting the resulting product. 323 A third radiotracer, [ 18 F]-FEPPA, can be efficiently synthesized in a single step by reacting its tosylate precursor with [ 18 F]KF/K 222 . 328 PET imaging can provide valuable insight into the extent of neurodegeneration and the impact on neurotransmission.…”

“…Five major classes of PET tracers for apoptosis − were used to study information on the temporal life cycle of apoptosis associated with early exposure to general anesthesia, namely PET tracers targeting caspase-3/7 activation; phosphorus cation-based PET tracers to assess mitochondrial membrane potential; PET tracers to detect plasma membrane phospholipid asymmetry and phosphatidylserine exposure; PET tracers targeting the plasma membrane depolarizing molecules; and PET tracers that can accumulate in apoptotic cells. The absorption and retention of 3′-deoxy-3′-[ 18 F]­fluoro­thymidine ([ 18 F]­FLT, [ 18 F] 61 ; RCY = 16 ± 2% (decay-corrected), RCP > 99%) provide the activity of thymidine kinase-1, which can be used as a non-invasive biomarker of cell proliferation. , [ 18 F] 61 has been used for non-invasive monitoring of endogenous neural stem cell proliferation in normal and ischemic adult rat brains in vivo . , 18 F-Labeled N -2-(2-fluoroethoxy)­benzyl)- N -(4-phenoxypyridin-3-yl)­acetamide ([ 18 F]­FEPPA, [ 18 F] 62 ; RCY = 34 ± 2% ( n = 17), RCP > 99%, A m = 198 ± 125 GBq/μmol), a specific translocation protein (TSPO) ligand, has been used as a marker of microglial activation as a surrogate marker of neural injury. ,,− Their physicochemical properties are described in Table .…”

“…The radiotracer [ 18 F] 60 can be synthesized by coupling 4-(fluoro- 18 F)­benzaldehyde with 5-(dimethylamino)­naphthalene-1-sulfonohydrazide (Scheme ). Another radiotracer, [ 18 F] 61 , can be prepared by first labeling a precursor with 18 F and then deprotecting the resulting product . A third radiotracer, [ 18 F]-FEPPA, can be efficiently synthesized in a single step by reacting its tosylate precursor with [ 18 F]­KF/K 222 …”