This thesis deals with the synthesis and development of 18F-labelled alkyl etomidate and vorozole analogues, and their use as positron emission tomography (PET) tracers for the imaging of the steroid enzymes 11β-hydroxylase and aromatase. Two synthetic 18F-labelling approaches to the etomidate and vorozole analogues were developed, and the analogues were evaluated in some biological assays.
The two-step labelling method was used to synthesise many compounds for biological evaluation. In the first step, a 18F-labelled intermediate based on a ditosylate or a halogenated diethyl ether was synthesised and used directly in the next alkylation step. The decay-corrected (d.c.) radiochemical yield was higher compared to other known two-step labelling methods.
Once an appropriate candidate has been chosen for clinical evaluation, a one-step labelling method will be more suitable. We therefore developed a method based on precursors that had leaving groups at the end of their alkyl chains, and used these directly in the 18F-labelling synthesis. The one-step 18F-labelling synthesis required less reaction time and produced higher specific radioactivity and d.c. radiochemical yield than our two-step synthesis. With microwave heating, the reaction time was reduced to seconds and the d.c. radiochemical yield was better than that obtained with conventional heating. The one-step synthesis simplified the technical handling by allowing the tracer syntheses to be automated on the TRACERLab FXFN.
By replacing the alkyl chain in a metomidate ester with F-18-labelled di- or tri(ethylene glycol) chains, two F-18-labelled PET tracers, i.e. 2-(2-[F-18]fluoroethoxy)ethyl 1-[(1R)-1-phenylethyll-1 H-imidazole-5-carboxylate (1) and 2-[2-(2-[F-18]fluoroethoxy)-ethoxylethyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (2), were synthesized. Two precursors, 2-(2-bromoethoxy)ethyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate and 2-[2-(2-chloroethoxy)ethoxylethyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate, were prepared and used in one-step nucleophilic [F-18]fluorination reactions using conventional and microwave heating. Organ distribution, frozen section autoradiography and metabolite analysis were performed. The decay-corrected radiochemical yields of 1 and 2 were 26 +/- 8 and 23 +/- 8%, respectively, when they were prepared using conventional heating. By performing microwave heating, the reaction time could be decreased and the yields of analogues 1 and 2 could be increased to 57 +/- 12 and 51 +/- 18%, respectively. Organ distribution studies in the rat showed considerable uptake in the lungs, adrenals and liver. Both compounds bound with low nonspecific binding (1: approx. 20-30%; 2: 2.9% or lower) to tissue from pig and human normal and pathologic adrenals. Metabolite analyses were performed in rats after 5 and 30 min for tracer 1 (20 +/- 6 and 2 +/- 1 %) and tracer 2 (27 +/- 5 and 6 +/- 4%). Both compounds are interesting candidates for the detection of different types of adrenal disorders.
Introduction: Two- and one-step syntheses of 18F-labelled analogues of Metomidate, such as 2-[18F]fluoroethyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (1), 2-[18F]fluoroethyl 1-[(1R)-1-(4-chlorophenyl)ethyl]-1H-imidazole-5-carboxylate (2), 2-[18F]fluoroethyl 1-[(1R)-1-(4-bromophenyl)ethyl]-1H-imidazole-5-carboxylate (3), 3-[18F]fluoropropyl 1-[(1R)-1-(4-bromophenyl)ethyl]-1H-imidazole-5-carboxylate (4) and 3-[18F]fluoropropyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (5) are presented.
Methods: Analogues 1-5 were prepared by a two-step reaction sequence that started with the synthesis of either 2-[18F]fluoroethyl 4-methylbenzenesulfonate or 3-[18F]fluoropropyl 4-methylbenzenesulfonate. These were used as 18F-alkylating agents in the second step, in which they reacted with the ammonium salt of a 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylic acid. One-step-labelling syntheses of 1, 2 and 5 were also explored. Analogues 1-4 were biological validated by frozen-section autoradiography and organ distribution. Metabolite analysis was performed for 2 and 3.
Results: The radiochemical yield of the two-step synthesis was in the range of 10-29%, and thatof the one-step synthesis was 25-37%. Using microwave irradiation in the one-step synthesis of 1 and 2 increased the radiochemical yield to 46 ± 3 and 79 ± 30%, respectively.
Conclusion: Both the frozen-section autoradiography and organ distribution results indicated that analogue 2 has a potential as an adrenocortical imaging agent, having the highest degree of specific adrenal binding and best ratio of adrenal to organ uptake among the compounds studied.
18F-Labelled analogues of three biologically interesting compounds, ethyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (ETO), 6-[(S)-(4-chlorophenyl)-(1H)-1,2,4-triazol-1-yl)methyl]-1-methyl-1H-benzotriazole (VOZ) and 7-methoxy-1-methyl-9H-β-carboline (HAR) were synthesized by one-step nucleophilic fluorination. The 18F-labelled products were obtained with 20–30% isolated decay-corrected radiochemical yields and the radiochemical purities were over 99% in all cases. The labelling syntheses were performed using fully automated commercial synthesizer TRACERLab FXFN. The automation of the syntheses of these three promising PET tracers using a commercial synthesizer will make them accessible for clinical applications.