Radiosynthesis of [124I]iodometomidate and biological evaluation using small-animal PET.

Purpose: The application of radiolabelled inhibitors of cytochrome P450 enzymes is a novel approach for molecular imaging of adrenocortical masses to detect adrenal tumours. One potential tracer is radiolabelled iodometomidate (IMTO) with a common option for scintigraphic diagnosis and therapeutic applications. The aim of this study was to radiolabel iodometomidate with the positron-emitting radionuclide iodine-124 ((124)I) for the investigation of the biological behaviour and pharmacokinetics with positron emission tomography (PET).

[(3)H]metyrapol and 4-[(131)i]iodometomidate label overlapping, but not identical, binding sites on rat adrenal membranes.

Metyrapone, metyrapol, and etomidate are competitive inhibitors of 11-deoxycorticosterone hydroxylation by 11β-hydroxylase. [(3)H]Metyrapol and 4-[(131)I]iodometomidate bind with high affinity to membranes prepared from bovine and rat adrenals. Here we report inhibitory potencies of several compounds structurally related to one or both of these adrenostatic drugs, against the binding of both radioligands to rat adrenal membranes.

Structure-activity relationship of etomidate derivatives at the GABA(A) receptor: Comparison with binding to 11beta-hydroxylase.

At the GABA(A) receptor, low concentrations of etomidate potentiate the inhibitory effect of GABA on specific binding of the closed channel ligand [(3)H]ethynylpropylbicycloorthobenzoate ([(3)H]EBOB). Here, we present SARs for etomidate and structurally related compounds inducing this effect. In the absence of GABA, similar SARs, but 14-20 times weaker potencies were observed.

New selective inhibitors of steroid 11beta-hydroxylation in the adrenal cortex. Synthesis and structure-activity relationship of potent etomidate analogues.

Derivatives of etomidate were evaluated as inhibitors of adrenal steroid 11beta-hydroxylations. Stereoselective coupling by Mitsunobu produced chirally pure analogues to study the effect of configuration, modification of the ester, and substitution in the phenyl ring, with the aim to probe specific sites for introducing a radionuclide. Iodophenyl metomidate (IMTO) labeled with iodine-131 served as radioligand for structure-affinity relationship studies.

Pharmacokinetics of 2-methoxyphenylmetyrapone and 2-bromophenylmetyrapone in rats.

The pharmacokinetics of two 2-substituted phenylmetyrapone analogues, 2-methoxyphenylmetyrapone (2-MPMP) and 2-bromophenylmetyrapone (2-BrPMP), developed as potential adrenal imaging agents, were investigated in conscious male rats following an intravenous dose of 25 mg/kg. Arterial blood samples (0.25 ml) were collected at various intervals for up to 7 h after dose and subjected to reversed-phase HPLC analysis.