title: Synthesis of [¹¹C]PBR06 and [¹⁸F]PBR06 as agents for positron emission tomographic (PET) imaging of the translocator protein (TSPO).
abstract: The translocator protein 18 kDa (TSPO) is an attractive target for molecular imaging of neuroinflammation and tumor progression. [(18)F]PBR06, a fluorine-18 labeled form of PBR06, is a promising PET TSPO radioligand originally developed at NIMH. [(11)C]PBR06, a carbon-11 labeled form of PBR06, was designed and synthesized for the first time. The standard PBR06 was synthesized from 2,5-dimethoxybenzaldehyde in three steps with 71% overall chemical yield. The radiolabeling precursor desmethyl-PBR06 was synthesized from 2-hydroxy-5-methoxybenzaldehyde in five steps with 12% overall chemical yield. The target tracer [(11)C]PBR06 was prepared by O-[(11)C]methylation of desmethyl-PBR06 with [(11)C]CH(3)OTf in CH(3)CN at 80°C under basic condition and isolated by HPLC combined with SPE purification with 40-60% decay corrected radiochemical yield and 222-740 GBq/μmol specific activity at EOB. On the similar grounds, [(18)F]PBR06 was also designed and synthesized. The previously described Br-PBR06 precursor was synthesized from 2,5-dimethoxybenzaldehyde in two steps with 78% overall chemical yield. A new radiolabeling precursor tosyloxy-PBR06, previously undescribed tosylate congener of PBR06, was designed and synthesized from ethyl 2-hydroxyacetate, 4-methylbenzene-1-sulfonyl chloride, and N-(2,5-dimethoxybenzyl)-2-phenoxyaniline in four steps with 50% overall chemical yield. [(18)F]PBR06 was prepared by the nucleophilic substitution of either new tosyloxy-PBR06 precursor or known Br-PBR06 precursor in DMSO at 140°C with K[(18)F]F/Kryptofix 2.2.2 for 15 min and HPLC combined with SPE purification in 20-60% decay corrected radiochemical yield, >99% radiochemical purity, 87-95% chemical purity, and 37-222 GBq/μmol specific activity at EOB. Radiosynthesis of [(18)F]PBR06 using new tosylated precursor gave similar radiochemical purity, and higher specific activity, radiochemical yield and chemical purity in comparison with radiosynthesis using bromine precursor.
authors.affiliation: Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 1345 West 16th Street, L3-202, Indianapolis, IN 46202-2111, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Mingzhang
authors.initials: M
authors.lastname: Gao
authors.forename: Kathy D
authors.initials: KD
authors.lastname: Miller
authors.forename: Qi-Huang
authors.initials: QH
authors.lastname: Zheng
mesh_terms: D000083:Acetanilides / Q000138:chemical synthesis*; D002250:Carbon Radioisotopes; D004660:Encephalitis / Q000000981:diagnostic imaging; D005462:Fluorine Radioisotopes / Q000737:chemistry; D006801:Humans; D057054:Molecular Imaging / Q000379:methods*; D009369:Neoplasms / Q000000981:diagnostic imaging; D049268:Positron-Emission Tomography / Q000379:methods*; D018079:Receptors, GABA / Q000032:analysis*
chemical_list: D000083:Acetanilides; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; C538798:N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline; D018079:Receptors, GABA; C499229:TSPO protein, human