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.

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.

Two ¹⁸F-labeled analogues of vorozole ([¹⁸F]FVOZ and [¹⁸F]FVOO) have been developed as potential tools for the in vivo characterization of aromatase. The purpose of the project was to evaluate the pharmacological properties of these radioligands using a combination of in vitro binding and in vivo distribution studies in the rat and primate. Saturation binding studies with the radioligands in homogenates of rat ovary gave K_D and B_max values of 0.21 ± 0.1 nM and 210 ± 20 fmol/mg, respectively, for [¹⁸F]FVOZ, and 7.6 ± 1 nM and 293 ± 12 fmol/mg, respectively, for [¹⁸F]FVOO. Organ distribution studies in rats showed the highest accumulation in the adrenal glands, with standardized uptake values (SUVs) of 15 to 20, followed by ovaries and liver with SUVs of approximately 5. The SUVs in the remaining organs were between 0.5 and 1.5. There was probably some defluorination of both radioligands, as the accumulation of radioactivity in bone increased with time. The regional distribution in the brain was studied using ex vivo and in vitro autoradiography. In the brain, specific binding of both [¹⁸F]FVOZ and [¹⁸F]FVOO were found mainly in the amygdala. PET studies were performed in the Rhesus monkey, and these showed displaceable binding in the amygdala and the preoptic area of the hypothalamus. These studies suggest that [¹⁸F]FVOZ might be to be a suitable tracer for the study of aromatase in vitro and in vivo, and could be an alternative to [¹¹C]vorozole in human PET-studies.

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 FX_FN. The automation of the syntheses of these three promising PET tracers using a commercial synthesizer will make them accessible for clinical applications.