18F]-(fluoromethoxy)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)propan-2-ol ([18F FPTC) a novel PET-ligand for cerebral beta-adrenoceptors

Abstract

Cerebral β-adrenergic receptors (β-ARs) play important roles in normal brain and changes of β-AR expression are associated with several neuropsychiatric illnesses. Given the high density of β-AR in several brain regions, quantification of β-AR levels using PET is feasible. However, there is a lack of radiotracers with suitable biological properties and meeting safety requirements for use in humans. We developed a PET tracer for β-AR by (18)F-fluorination of 1-((9H-carbazol-4-yl)oxy)-3-4(4-((2-(2-(fluoromethoxy)-ethoxy)methyl)-1H-1,2,3-triazol-1-yl)propan-2-ol ((18)F-FPTC). [(18)F] FPTC was synthesized by Cu(I)-catalyzed alkyne-azide cycloaddition. First, (18)F-PEGylated alkyne was prepared by (18)F-fluorination of the corresponding tosylate. Next (18)F-PEGylated alkyne was reacted with an azidoalcohol derivative of 4-hydroxycarbazol in the presence of the phosphoramidite Monophos as a ligand and Cu(I) as a catalyst. After purification with radio-HPLC, the binding properties of [(18)F FPTC were tested in β-AR-expressing C6-glioma cells in vitro and in Wistar rats in vivo using microPET. The radiochemical yield of (18)F-PEGylated alkyne was 74%-89%. The click reaction to prepare [(18)F]FPTC proceeded in 10min with a conversion efficiency of 96%. The total synthesis time was 55min from the end of bombardment. Specific activities were >120GBq/μmol. Propranolol strongly and dose-dependently inhibited the binding of both [(125)I]-ICYP and [(18)F]FPTC to C6 glioma cells, with IC50 values in the 50-60 nM range. However, although both FPTC and propranolol inhibited cellular [(125)I]ICYP binding, FPTC decreased [(125)I]ICYP uptake by only 25%, whereas propranolol reduced it by 83%. [(18)F]FPTC has the appropriate lipophilicity to penetrate the blood brain barrier (logP +2.48). The brain uptake reached a maximum within 2min after injection of 20-25MBq [(18)F]FPTC. SUV values ranged from 0.4 to 0.6 and were not reduced by propranolol. Cerebral distribution volume of the tracer (calculated from a Logan plot) was increased rather than decreased after propranolol treatment. 'Click chemistry' was successfully applied to the synthesis of [(18)F]FPTC resulting in high radiochemical yields. [(18)F]FPTC showed specific binding in vitro, but not in vivo. Based on the logP value and its ability to block [(125)I]ICYP binding to C6 cells, FPTC may be a lead to suitable cerebral β-AR ligands.