Synthesis and in vitro evaluation of ¹⁸F‐labelled di‐ and tri(ethylene glycol) metomidate esters

Abstract

By replacing the alkyl chain in a metomidate ester with 18 F]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 2678 and 2378%, 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 57712 and 51718%, 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 (2076 and 271%) and tracer 2 (2775 and 674%). Both compounds are interesting candidates for the detection of different types of adrenal disorders.

Effect of the Prosthetic Group on the Pharmacologic Properties of 18F-Labeled Rhodamine B, a Potential Myocardial Perfusion Agent for Positron Emission Tomography (PET)

“…38–39 These investigators found that the ethyl ester was slightly more stable in vivo than the diethylene glycol ester, and that the difference between stability of the triethylene and diethylene glycol esters was minimal.…”

“…These investigators also measured the metabolic stability of the diethylene and triethylene glycol esters of metomidate in rats and found that only 2% of the diethylene glycol ester remained intact at 30 min after injection compared to 6% of the triethylene glycol ester. 39 In combination, these results suggest, somewhat unexpectedly, that changing the ester group has minimal impact on the in vivo stability of these compounds.…”

“…In this context, it is worth noting that this is one of the few examples where diethylene glycol (or triethylene glycol) has been used as a prosthetic group for labeling a compound with 18 F. These results are somewhat disparate from those obtained by Erlandsson et al in their studies of ethyl esters of chloro-and bromometomidate and of the of the triethylene and diethylene glycol esters of metomidate. 38,39 These investigators found that the ethyl ester was slightly more stable in vivo than the diethylene glycol ester and that the difference between stability of the triethylene and diethylene glycol esters was minimal.…”

Automated synthesis of 18F‐labelled analogs of metomidate, vorozole and harmine using commercial platform

“…11 C-Labelled analog of harmine was used to detect the high expression of MAO-A in neuroendocrine gastroenteropancreatic tumor. 10 18 F-Labelled analogs of these tracers, metomidate, 11,12 vorozole 13 and harmine 14 have recently been developed and evaluated as PET tracers. The previous papers described the syntheses on the semi-automated platform Synthia 15 developed at Uppsala University PET center.…”

Radiochemistry

“…But most improvements involve the introduction of automated procedures, as in the labelling of fluorodeoxyglucose, 131,132 fluoro-L-DOPA, 133 16a-[F 18 ]fluoroestradiol, 134 [F 18 ]fluoroethylcholine, 135 [F 18 ]fluorotetracosactide, 136 9-(4-[F 18 ]fluoro-3-hydroxymethylbutyl)guanine, 137 substituted nitroimidazoles, 138 a range of fluorinated arabinofuranosyluracils 139 and even sodium [F 18 ]fluoride 140 itself. Other molecules labelled with fluorine-18 have included N-succinimidyl-4-fluorobenzoate, 141 ethyleneglycol metomidate esters, 142 tyrosine 143 and cysteine 144 derivatives for tumour imaging, flumazenil, 145,146 2-fluoro-3-(hex-5-ynyloxy)pyridine 147 and 2 0 fluoro-5-iodo-1-b-D-arabinofuranosylcytosine, 148 both for use in protein labelling, as well as [F 18 ]altanserin 149 for plasma metabolite studies, N,N-dimethyl-2-(2-amino-4-fluorophenylthio)benzylamine, 150 for serotonin imaging and the muscarinic M2 radiopharmaceutical, FP-TZTP. 151 Phosphorus (P 32 & P 33 ) and sulfur (S 35 )…”