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

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 design: For 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.

Results: In 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.

Conclusions: 18F-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 registration: ClinicalTrials.gov NCT01186601.

Conflict of interest statement

Competing Interests: The authors have the following interests: The study was sponsored by Bayer Healthcare. NK, AM, MB, HSW, VG, MF, LMD, AWS, LMF, and CBS were employed by Bayer Pharma AG at the time of study conduct. NK, AM, MB, SB, HSW, MF, LMD, and AWS are currently employed by Piramal Imaging GmbH. On the basis of prior work, patent applications were filed from Bayer to cover the compound investigated here. The compound rights were transferred to Piramal Imaging. The investigated compound is currently in clinical development and is not marketed. NK, AM, MB, HSW, AWS, MF, LMD are co-inventors of the compound and/or have ownership interests in Piramal Imaging. DHM, ESM and SSG received research grants from Bayer Healthcare and Piramal Imaging related to this compound. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Fig 1. CONSORT Participant Flow Diagram.

Fig 2

PET imaging of rat GS9L brain tumors with (A) 18F-FSPG (B) 18F-FDG and (C) 18F-FET. Selected sagittal (upper images) and coronal (lower images) slices are shown (dose: 15 MBq each, imaging time: 0–30 min p.i.).

Fig 3. Time-activity curves of 18F-FSPG, 18F-FDG and 18F-FET tumor-uptake ratio in orthotopic GS9L rat brain tumor lesions.

A volume of interest (VOI) analysis over time was performed from the tumor lesions and the ratio calculated using the VOI from the healthy brain for each tracer. 18F-FSPG showed increasing VOI ratio activity over time. In contrast, 18F-FDG and 18F-FET VOI ratios remained rather constant and at a lower level.

Fig 4. Comparison of axial post-contrast T1 MRI (left column) and 18F-FSPG PET (right column) in the two subjects with primary brain tumor.

Subject A has recurrent high-grade glioblastoma, while subject B has an enlarging, partially resected low-grade oligodendroglioma. In each case, the arrows point to the primary lesions. For subject A, there is intense accumulation of 18F-FSPG in the enhancing lesion (SUV 5.2), while in subject B, there is no accumulation of the radiotracer (SUV 0.7) in the non-enhancing lesion. Comparatively, the background brain SUV is 0.1 for both subjects. There is incidental note of prominent physiologic uptake of 18F-FSPG in the scalp.

Fig 5. 18F-FSPG PET images, in comparison with MRI and 18F-FDG PET images of the three patients with lung cancer metastases to the brain.

For each subject, the whole-body Maximum Intensity Projection (MIP) image of the 18F-FSPG PET scan is shown on the left. In the right column, the axial images through the level of the brain metastasis include the post-contrast T1 MRI (top), 18F-FSPG PET (middle), and 18F-FDG PET (bottom). Physiologic distribution to normal organs are highlighted on the MIP image for subject A, including the liver (l), pancreas (p), kidneys (k), and bladder (b). For the first two subjects (A, B), the small lesions (below 1.5 cm) are clearly visible on MRI and with 18F-FSPG (SUV-A: 11.0, SUV-B: 4.7). With 18F-FDG, however, there is no discernible activity in these lesions. The larger lesion for subject C, who had previously been treated in this region, is again clearly discernable with MRI although the etiology of the enhancement was unclear whether representing residual/recurrent disease versus post-therapy changes. Both the 18F-FDG (SUV 10.1) and 18F-FSPG PET (SUV 21.8) are positive for this subject, but the accumulation of the latter is stronger, and further enhanced by the lack of uptake in the surrounding normal brain tissue (FDG SUV 4.8, FSPG SUV 0.1).