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

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). Methods: [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. Results: The radiochemical yield of 18 F‐PEGylated alkyne was 74%–89%. The click reaction to prepare [18 F]FPTC proceeded in 10 min with a conversion efficiency of 96%. The total synthesis time was 55 min from the end of bombardment. Specific activities were > 120 GBq/μmol. Propranolol strongly and dose-dependently inhibited the binding of both [125I]-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 [125I]ICYP binding, FPTC decreased [125I]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 2 min after injection of 20–25 MBq [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. Conclusion: '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 [125I]ICYP binding to C6 cells, FPTC may be a lead to suitable cerebral β-AR ligands