Radioiodination of Aryl-Alkyl Cyclic Sulfates

Chandra Mushti,Mikhail Papisov

doi:10.3390/molecules171113266

Abstract

Among the currently available positron emitters suitable for Positron Emission Tomography (PET), 124I has the longest physical half-life (4.2 days). The long half-life and well-investigated behavior of iodine in vivo makes 124I very attractive for pharmacological studies. In this communication, we describe a simple yet effective method for the synthesis of novel 124I labeled compounds intended for PET imaging of arylsulfatase activity in vivo. Arylsulfatases have important biological functions, and genetic deficiencies of such functions require pharmacological replacement, the efficacy of which must be properly and non-invasively evaluated. These enzymes, even though their natural substrates are mostly of aliphatic nature, hydrolyze phenolic sulfates to phenol and sulfuric acid. The availability of [124I]iodinated substrates is expected to provide a PET-based method for measuring their activity in vivo. The currently available methods of synthesis of iodinated arylsulfates usually require either introducing of a protected sulfate ester early in the synthesis or introduction of sulfate group at the end of synthesis in a separate step. The described method gives the desired product in one step from an aryl-alkyl cyclic sulfate. When treated with iodide, the source cyclic sulfate opens with substitution of iodide at the alkyl center and gives the desired arylsulfate monoester.

Highlights

Arylsulfatases [1] are a group of lysosomal enzymes responsible for hydrolyzing the sulfate ester group esters in various biological substrates
We conducted several preclinical studies where radiolabeled enzyme molecules were studied by Positron Emission Tomography (PET) to determine the kinetics of their transfer from the injection point to the organs of interest [6,7]
We have investigated the pharmacokinetics of arylsulfatase A (ARSA) in rodents [7] and non-human primates [9], which provided the pharmacokinetics data necessary for estimating the initial enzyme deposition in the tissue as a function of administration modality

Summary

Introduction

Arylsulfatases [1] are a group of lysosomal enzymes responsible for hydrolyzing the sulfate ester group esters in various biological substrates. E.g., 4-nitrocatechol sulfate and 4-methylumbelliferyl sulfate (Figure 1, 2 and 3), are known to be hydrolyzed by ARSA (as well as other arylsulfatases) under physiological conditions They give colored and fluorescent products upon desulfation [12], respectively, which enables their use in in vitro assays of arylsulfatase activity. One of the major hurdles in designing compounds suitable for use as substrates for arylsulfatases is the introduction of the sulfate ester This group is sensitive to acidic conditions and is known to undergo nucleophilic substitution when present on an alkyl scaffold. The currently available procedures usually utilize either the introduction of sulfate ester at the end of the synthetic sequence, or introducing a protected sulfate ester at the beginning, followed by removal of the protection at the end of the sequence These methods are attractive for the synthesis of sulfate esters of stable compounds, they are not optimal for radiochemical syntheses. We report a new method for synthesis of radioiodinated arylsulfatase substrates, where the introduction of the radiolabel (124I) and formation of the sulfate ester are achieved in one step

Results and Discussion

Experimental

Conclusions