Pilot Preclinical and Clinical Evaluation of (4S)-4-(3-[18F]Fluoropropyl)-L-Glutamate (18F-FSPG) for PET/CT Imaging of Intracranial Malignancies.

Erik Mittra ,Santiago Bullich,Frederick T Chin,Claudia Bacher-Stier,Khun Visith Keu,Sanjiv S Gambhir,Matthias Friebe,Mathias Berndt,Norman Koglin,Dae Hyuk Moon,Aileen Hoehne,Volker Gekeler,Camila Mosci,Meena Kumar,Andrei Iagaru ,Ludger Dinkelborg ,André Mueller ,Andrew Stephens ,Lüder Fels ,Heribert Schmitt‐Willich

doi:10.1371/journal.pone.0148628

Abstract

Purpose(S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid (18F-FSPG) is a novel radiopharmaceutical for Positron Emission Tomography (PET) imaging. It is a glutamate analogue that can be used to measure xC- transporter activity. This study was performed to assess the feasibility of 18F-FSPG for imaging orthotopic brain tumors in small animals and the translation of this approach in human subjects with intracranial malignancies.Experimental DesignFor the small animal study, GS9L glioblastoma cells were implanted into brains of Fischer rats and studied with 18F-FSPG, the 18F-labeled glucose derivative 18F-FDG and with the 18F-labeled amino acid derivative 18F-FET. For the human study, five subjects with either primary or metastatic brain cancer were recruited (mean age 50.4 years). After injection of 300 MBq of 18F-FSPG, 3 whole-body PET/Computed Tomography (CT) scans were obtained and safety parameters were measured. The three subjects with brain metastases also had an 18F-FDG PET/CT scan. Quantitative and qualitative comparison of the scans was performed to assess kinetics, biodistribution, and relative efficacy of the tracers.ResultsIn the small animals, the orthotopic brain tumors were visualized well with 18F-FSPG. The high tumor uptake of 18F-FSPG in the GS9L model and the absence of background signal led to good tumor visualization with high contrast (tumor/brain ratio: 32.7). 18F-FDG and 18F-FET showed T/B ratios of 1.7 and 2.8, respectively. In the human pilot study, 18F-FSPG was well tolerated and there was similar distribution in all patients. All malignant lesions were positive with 18F-FSPG except for one low-grade primary brain tumor. In the 18F-FSPG-PET-positive tumors a similar T/B ratio was observed as in the animal model.Conclusions18F-FSPG is a novel PET radiopharmaceutical that demonstrates good uptake in both small animal and human studies of intracranial malignancies. Future studies on larger numbers of subjects and a wider array of brain tumors are planned.Trial RegistrationClinicalTrials.gov NCT01186601

Highlights

Primary and secondary brain tumors are of major medical importance as they almost always have very poor clinical outcomes
Metabolic imaging with 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography coupled with computed tomography (PET/Computed tomography (CT)), has a limited role in the diagnosis of intracranial malignancy as the high physiologic 18F-FDG uptake in normal brain limits and reduces its sensitivity [10]
Radiolabeling of 18F-FSPG was accomplished by nucleophilic substitution of the nosylate precursor di-tert-butyl (4S)-N-(tert-butoxycarbonyl)-4-(3{[(4-nitrophenyl) sulfonyl]oxy}-propyl)-L-glutamate using K18F kryptofix complex and subsequent acidic deprotection followed by cartridge purification. 18F-FDG for preclinical studies was obtained from Eckert & Ziegler Euro-Positron Emission Tomography (PET) GmbH (Berlin, Germany). 18F-FET was provided by IASON PET-Network (Graz, Austria)

Summary

Introduction

Primary and secondary brain tumors are of major medical importance as they almost always have very poor clinical outcomes. The anatomic diagnostic modality of choice for the initial diagnosis and subsequent followup of brain tumors is magnetic resonance imaging (MRI) [5, 6]. MR has limitations, especially in the sensitivity of smaller lesions and in the specificity for the evaluation of the post-treatment brain [7]. Metabolic imaging with 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography coupled with computed tomography (PET/CT), has a limited role in the diagnosis of intracranial malignancy as the high physiologic 18F-FDG uptake in normal brain limits and reduces its sensitivity [10]. In the post-treatment setting, especially after radiation therapy, 18F-FDG PET can be used to distinguish between radiation necrosis and residual / recurrent tumor [10]. In an attempt to overcome some of these limitations with 18F-FDG, a variety of different amino acid-based radiopharmaceuticals have been investigated including methyl11C-L-methionine (11C-MET), O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET), 6-18F-fluoro-Ldopa (18F-FDOPA), and 18F-fluoro-L-thymidine (18F-FLT) [11], and most recently, 4-18F(2S,4R)-fluoroglutamine (18F-FGln) [12]

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