18F-FBPA as a tumor-specific probe of L-type amino acid transporter 1 (LAT1): a comparison study with 18F-FDG and 11C-Methionine PET
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The purpose of this study was to evaluate the usefulness of L-4-borono-2-18F-fluoro-phenylalanine (18F-FBPA) as a tumor-specific probe, in comparison to 18F-FDG and 11C-methionine (Met), focusing on its transport selectivity by L-type amino acid transporter 1 (LAT1), which is highly upregulated in cancers.
Cellular analyses of FBPA were performed to evaluate the transportablity and Km value. PET studies were performed in rat xenograft models of C6 glioma (n = 12) and in rat models of turpentine oil-induced subcutaneous inflammation (n = 9). The kinetic parameters and uptake values on static PET images were compared using the one-tissue compartment model (K1, k2) and maximum standardized uptake value (SUVmax).
The cellular analyses showed that FBPA had a lower affinity to a normal cell-type transporter LAT2 and induced less efflux through LAT2 among FBPA, Met, and BPA, while the efflux through LAT1 induced by FBPA was similar among the three compounds. The Km value of 18F-FBPA for LAT1 (196.8 ± 11.4 μM) was dramatically lower than that for LAT2 (2813.8 ± 574.5 μM), suggesting the higher selectivity of 18F-FBPA for LAT1. K1 and k2 values were significantly smaller in 18F-FBPA PET (K1 = 0.04 ± 0.01 ml/ccm/min and k2 = 0.07 ± 0.01 /min) as compared to 11C-Met PET (0.22 ± 0.09 and 0.52 ± 0.10, respectively) in inflammatory lesions. Static PET analysis based on the SUVmax showed significantly higher accumulation of 18F-FDG in the tumor and inflammatory lesions (7.2 ± 2.1 and 4.6 ± 0.63, respectively) as compared to both 18F-FBPA (3.2 ± 0.40 and 1.9 ± 0.19) and 11C-Met (3.4 ± 0.43 and 1.6 ± 0.11). No significant difference was observed between 18F-FBPA and 11C-Met in the static PET images.
This study shows the utility of 18F-FBPA as a tumor-specific probe of LAT1 with low accumulation in the inflammatory lesions.
KeywordsPET LAT1 Glioma Inflammation Rat model
We would like to thank all members of the PET Drug Synthesis Department in Osaka University Hospital for the preparation of tracers, Mitsunori Kirihata for providing non-radiolabeled FBPA, Genki Horitsugi, Keiko Matsunaga, Kayako Isohashi, Hiroki Kato, and Mitsuaki Tatsumi for their assistance, other members of department of Bio-system Pharmacology and department of Nuclear Medicine for supporting the experiments in PET Molecular Imaging Center, and Hiroaki Tanigawa, Rumi Saika, and Miyuki Kuroi for excellent technical assistance.
Compliance with Ethical Standards
This study was funded by KAKENHI Grant-in-Aid for Scientific Research (S) (Number 24229008) and (A) (Number 24249077) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.
Conflict of interest
No other potential conflict of interest relevant to this article was reported.
All the animal experiments were performed in compliance with the guidelines of the Institute of Experimental Animal Sciences. The protocol was approved by the Animal Care and Use Committee of the Osaka University Graduate School of Medicine (Approval number: 20-144-008).
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