A metabolically stable leucine mimic identifies cancer from inflammation with positron emission tomography

Objectives Non-invasively differentiating tumor from inflammation is a long-standing challenge for cancer diagnosis. In clinics, a biopsy or surgery is often required to justify the malignancy of certain types of cancer. Previously, positron emission tomography (PET) with 18F-FDG is the standard non-invasive technique for cancer imaging. However, FDG highlights any tissue with high energy consumption and is not tumor-specific. In addition to accumulating in fast growing tumors, FDG accumulation may be observed in a variety of healthy tissues and ones affected by various non-neoplastic pathologic conditions, such as acute and chronic inflammations and infections. Herein we report a 18F-labeled boron-derived leucine derivative (B-Leu) to distinguish cancer from inflammation in living systems.

Methods A boron-derived leucine derivative was synthesized to mimic Leu, of which the transportation depends on L-type amino acid transporter (LAT). 18F-19F isotope exchange reaction was conducted for radiolabeling and quality control was performed by both HPLC and radioTLC. The metabolic stability of 18F-B-Leu was assessed both in vitro and in vivo. PET imaging and bio-distribution studies were performed in mice bearing UM22B xenografts on the right shoulder and inflammation in the left hind limb (Inflammation was introduced by intramuscular injection of turpentine 72 h prior to PET scan).

Results The intracellular uptake of B-Leu was highly selective and competed effectively with natural Leu. The cellular uptake of B-Leu increased when incubated with the transfected cells express higher level of LAT-1, and a nearly linear relationship was found between the cellular uptake of Leu and the LAT-1 expression. Remarkably, 18F-B-Leu is highly metabolically stable, which is a unique advantage because metabolism of imaging probe often results in low tumor-specificity with high background uptake. As expected, 18F-B-Leu showed high accumulation in UM22B tumor (12.5 ± 3.1 %ID/g) and low uptake in the rest of the body (liver, 2.23 ± 0.46 %ID/g; muscle, 2.01 ± 0.53 %ID/g; and blood, 1.49 ± 0.82%ID/g). The tracer had predominant renal clearance but with low kidney retention. In addition, representative PET images demonstrated that 18F-B-Leu does not accumulate, but 18F-FDG does accumulate, in the inflammation region.

Conclusions A boron-derived Leu derivative was developed and evaluated for targeting LAT-1 expression with PET. Administration of ¹⁸F-B-Leu allowed for clear visualization of tumor xenografts in mice, with almost negligible uptake in the inflammatory foci, suggesting a unique advantage over ¹⁸F-FDG, which is currently the gold standard PET tracer for clinical diagnosis. Figure: Compared with ¹¹C-Leu and ¹⁸F-FDG, ¹⁸F-B-Leu showed specific accumulation in the tumor, and notably lower uptake in other major organs and inflammatory lesion. (A), (B) and (C) Whole-body maximum intensity projection PET images of a UM22B bearing mouse showing the uptake of ¹¹C-Leu (A), ¹⁸F-B-Leu (B) and ¹⁸F-FDG (C). Tumor (t), bladder (b) and inflammation (i) were indicated by white arrows.

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