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

• Published in: Nuclear medicine and biology Vol. 41; no. 2; pp. 203 - 209
• Main Authors: Mirfeizi, Leila, Rybczynska, Anna A, Waarde, Aren van, Campbell-Verduyn, Lachlan, Feringa, Ben L, Dierckx, Rudi AJO, Elsinga, Philip H
• Format: Journal Article
• Language: English
• Published: 01.02.2014
• ISSN: 0969-8051
• DOI: 10.1016/j.nucmedbio.2013.10.011

Cerebral beta -adrenergic receptors ( beta -ARs) play important roles in normal brain and changes of beta -AR expression are associated with several neuropsychiatric illnesses. Given the high density of beta -AR in several brain regions, quantification of beta -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 beta -AR by super(18) F-fluorination of 1-((9H-carbazol-4-yl)oxy)-3-4(4-((2-(2-(fluoromethoxy)-ethoxy)meth y l)-1H-1,2,3-triazol-1-yl)propan-2-ol ( super(18) F-FPTC). Methods: [ super(18) F] FPTC was synthesized by Cu(I)-catalyzed alkyne-azide cycloaddition. First, super(18) F-PEGylated alkyne was prepared by super(18) F-fluorination of the corresponding tosylate. Next super(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 [ super(18) F FPTC were tested in beta -AR-expressing C6-glioma cells in vitro and in Wistar rats in vivo using microPET. Results: The radiochemical yield of super(18) F-PEGylated alkyne was 74%-89%. The click reaction to prepare [ super(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/ mu mol. Propranolol strongly and dose-dependently inhibited the binding of both [ super(125)I]-ICYP and [ super(18) F]FPTC to C6 glioma cells, with IC sub(50) values in the 50-60 nM range. However, although both FPTC and propranolol inhibited cellular [ super(125)I]ICYP binding, FPTC decreased [ super(125)I]ICYP uptake by only 25%, whereas propranolol reduced it by 83%. [ super(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 [ super(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 [ super(18) F]FPTC resulting in high radiochemical yields. [ super(18) F]FPTC showed specific binding in vitro, but not in vivo. Based on the logP value and its ability to block [ super(125)I]ICYP binding to C6 cells, FPTC may be a lead to suitable cerebral beta -AR ligands.