Synthesis and Biological Evaluation of a Radiolabeled PET (Positron Emission Tomography) Probe for Visualization of In Vivo α-Fucosidase Expression.

Jonathan Cotton,Chris Marc Goehring,Andreas Maurer,Anna Kuehn,Bernd J Pichler,Kerstin Fuchs

doi:10.3390/ph14080745

Jonathan Cotton, Chris Marc Goehring + Show 4 more

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https://doi.org/10.3390/ph14080745

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Abstract

The acidic hydrolase α-fucosidase (AF) is a biomarker for maladies such as cancer and inflammation. The most advanced probes for α-fucosidase are unfortunately constrained to ex vivo or in vitro applications. The in vivo detection and quantification of AF using positron emission tomography would allow for better discovery and diagnosis of disease as well as provide better understanding of disease progression. We synthesized, characterized, and evaluated a radiolabeled small molecule inhibitor of AF based on a known molecule. The radiosynthesis involved the 11C methylation of a phenoxide, which was generated in situ by ultrasonification of the precursor with sodium hydride. The tracer was produced with a decay corrected yield of 41.7 ± 16.5% and had a molar activity of 65.4 ± 30.3 GBq/μmol. The tracer was shown to be stable in mouse serum at 60 min. To test the new tracer, HCT116 colorectal carcinoma cells were engineered to overexpress human AF. In vitro evaluation revealed 3.5-fold higher uptake in HCT116AF cells compared to HCT116 controls (26.4 ± 7.8 vs. 7.5 ± 1.0 kBq/106 cells). Static PET scans 50 min post injection revealed 2.5-fold higher tracer uptake in the HCT116AF tumors (3.0 ± 0.8%ID/cc (n = 6)) compared with the controls (1.2 ± 0.8 (n = 5)). Dynamic scans showed higher uptake in the HCT116AF tumors at all time-points (n = 2). Ex vivo analysis of the tumors, utilizing fluorescent DDK2 antibodies, confirmed the expression of human AF in the HCT116AF xenografts. We have developed a novel PET tracer to image AF in vivo and will now apply this to relevant disease models.

Highlights

Introduction published maps and institutional affilTools that can non-invasively detect metabolic alterations in vivo provide us with unique and profound opportunities in personalized medicine and offer insight into the cause, progression, and treatment of disease
Increased acidic hydrolase α-fucosidase (AF) expression can be associated with inflammation [1], cystic fibrosis [2], cancer [3,4,5,6], and Helicobacter pylori infection [7]
Access to the reference title compound 3 and the family of pyrrolidines outlined by Kotland relies on synthesis of the glycosylamine 5, which can be produced in five steps from commercially available D-ribose (Figure 1B) [10]

Summary

Introduction

Tools that can non-invasively detect metabolic alterations in vivo provide us with unique and profound opportunities in personalized medicine and offer insight into the cause, progression, and treatment of disease. Positron emission tomography (PET) is an imaging modality that offers high sensitivity and good spatial resolution, relying on the administration of radiolabeled biologically active molecules that can be detected in trace quantities. Through the use of PET probes, biological processes can be interrogated without effecting changes in the system being evaluated. Increased AF expression can be associated with inflammation [1], cystic fibrosis [2], cancer [3,4,5,6], and Helicobacter pylori infection [7]. AF mRNA expression levels in certain breast tumors have been shown to be iations

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