cis-4-[¹⁸F]-Fluoro-l-proline fails to detect peripheral tumors in humans

Abstract

System A amino acid transport is increased in transformed and malignant cells. The amino acid 4-cis[¹⁸F]fluoro-l-proline (cis-[¹⁸F]FPro) has been shown to be a substrate of the System A amino acid carrier. In this pilot study, we investigated the diagnostic potential of cis-[¹⁸F]FPro in patients with various tumors in comparison with [¹⁸F]fluorodeoxyglucose-positron emission tomography (FDG-PET).

Methods

Eight patients (seven females, one male, age range 43–77 years) with large primary, recurrent or metastatic tumors of different histologies were included in this study. One patient had a recurrent non-Hodgkin lymphoma; two patients, metastatic colon or rectal cancer; one, a metastatic endometrial cancer; one, a multiple myeloma; one, an Ewing sarcoma; one, a metastatic breast cancer and one, a gastrointestinal stromal tumor. PET scans of the trunk were acquired at 1 h after intravenous injection of 400 MBq cis-[¹⁸F]FPro and compared to PET scans with [¹⁸F]FDG.

Results

None of the tumors or metastatic lesions in this series of patients demonstrated relevant uptake of cis-[¹⁸F]FPro. In contrast, all tumors with exception of the multiple myeloma showed an intensive uptake of [¹⁸F]FDG. The mean standardized uptake value of cis-[¹⁸F]FPro in the tumor or metastases was significantly lower than that of [¹⁸F]FDG uptake (1.7±0.6 vs. 5.7±3.0; n=8; P<.01).

Conclusion

Although other System A-specific tracers have shown relevant tumor uptake, cis-[¹⁸F]FPro fails to detect most types of human tumors. Based on these results, we cannot recommend a further evaluation of this tracer as a tumor-seeking agent.

Introduction

Clinical cancer imaging with [¹⁸F]fluorodeoxyglucose (FDG) and positron emission tomography (PET) is rapidly expanding but there is also growing interest in new ¹⁸F-labelled tracers with more specific imaging characteristics. Promising candidates are for example 6-l-[¹⁸F]-fluorodihydroxyphenylalanine that exhibits a high specificity and sensitivity for neuroendocrine tumors [1], 3-deoxy-3-[¹⁸F]-fluorothymidine as a tracer of tumor proliferation [2] and [¹⁸F]-fluoromisonidazole as surrogate marker of tumor hypoxia [3]. Furthermore, radiolabeled amino acids, such as O-2-[¹⁸F]Fluorethyl)-l-tyrosine (FET), have shown superior results for brain tumor imaging compared with [¹⁸F]FDG especially for the determination of the size of cerebral gliomas, detection of tumor recurrences and prognosis in low-grade gliomas [4], [5], [6], [7].

The amino acid cis-4-[¹⁸F]fluoro-l-proline (cis-[¹⁸F]FPro) has been developed some years ago as a tracer for collagen synthesis because it is well known that l-proline represents a major constituent of collagen [8], [9]. PET imaging of pulmonary fibrosis with cis-[¹⁸F]FPro in a rabbit model indicated sensitive and specific identification of silicotic animals in early stages of the disease [10], [11], but another study evaluating cis-[¹⁸F]FPro in scar formation found no relationship of ¹⁸F-cis-FPro uptake to the content of connective tissue [12]. Experiments in tumor-bearing mice demonstrated that cis-[¹⁸F]FPro accumulates in osteosarcomas, mammary carcinomas and colon carcinomas and is incorporated into protein [9]. Some uptake of cis-[¹⁸F]FPro was observed in human brain tumors, which, however, was restricted to areas with blood–brain barrier disruption as indicated by contrast enhancing areas on computed tomography (CT) or magnetic resonance imaging after injection of contrast media [13]. No significant tumor uptake of cis-[¹⁸F]FPro, however, was found in a first series of patients with urologic tumors [14]. In vitro experiments demonstrated that cis-[¹⁸F]FPro and l-proline exhibit similar transport characteristics in F98 rat glioma cells, i.e., mainly Na⁺-dependent transport via amino acid transport systems A and B^0,+ [15]. It is known that system A is up-regulated in transformed and malignant cells and appears to be a target of proto-oncogene and oncogene action [16]. Substrates of system A such as [N-methyl-¹¹C]α-methylaminobutyric acid ([¹¹C]-MeAIB) have been shown to accumulate in lymphoma and head and neck tumors in humans [17], [18]. Since cis-[¹⁸F]FPro offers efficient radiosynthesis and, compared with [¹¹C]-MeAIB, the logistic advantage of labeling with the longer lived fluorine-18 (109 min half-life vs. 20 min for C-11) that allows the use of the tracer at PET units without an onsite cyclotron, we screened a series of patients with large tumors of different histopathology in order to further explore the diagnostic potential of this tracer.