Development of a Widely Usable Amino Acid Tracer: ⁷⁶Br-α-Methyl-Phenylalanine for Tumor PET Imaging

Abstract

Radiolabeled amino acids are superior PET tracers for the imaging of malignant tumors, and amino acids labeled with 76 Br, an attractive positron emitter because of its relatively long half-life (16.2 h), could potentially be a widely usable tumor imaging tracer. In this study, in consideration of its stability and tumor specificity, we designed two 76 Br-labeled amino acid derivatives, 2-76 Br-bromo-α-methyl-L-phenylalanine (2-76 Br-BAMP) and 4-76 Br-bromo-α-methyl-L-phenylalanine (4-76 Br-BAMP), and investigated their potential as tumor imaging agents. Methods: Both 76 Br-and 77 Br-labeled amino acid derivatives were prepared. We performed in vitro and in vivo stability studies and cellular uptake studies using the LS180 colon adenocarcinoma cell line. Biodistribution studies in normal mice and in LS180 tumor-bearing mice were performed, and the tumors were imaged with a small-animal PET scanner. Results: Both 77 BrBAMPs were stable in the plasma and in the murine body. Although both 77 Br-BAMPs were taken up by LS180 cells and the uptake was inhibited by L-type amino acid transporter 1 inhibitors, 2-77 Br-BAMP exhibited higher uptake than 4-77 Br-BAMP. In the biodistribution studies, 2-77 Br-BAMP showed more rapid blood clearance and lower renal accumulation than 4-77 Br-BAMP. More than 90% of the injected radioactivity was excreted in the urine by 6 h after the injection of 2-77 Br-BAMP. High tumor accumulation of 2-77 Br-BAMP was observed in tumor-bearing mice, and PET imaging with 2-76 Br-BAMP enabled clear visualization of the tumors. Conclusion: 2-77 Br-BAMP exhibited preferred pharmacokinetics and high LS180 tumor accumulation, and 2-76 Br-BAMP enabled clear visualization of the tumors by PET imaging. These findings suggest that 2-76 Br-BAMP could constitute a potential new PET tracer for tumor imaging and may eventually enable the wider use of amino acid tracers. Iti s well recognized that 18 F-FDG PET has had a great impact in tumor imaging and monitoring the response of tumors to chemotherapy. However, the high accumulations of 18 F-FDG that can occur in nontarget tissues such as the brain and inflammatory sites invoke the need for other PET tracers that could complement or replace 18 F-FDG (1,2). Among them, amino acid tracers such as 11 C-methionine, O-18 F-fluoromethyl-L-tyrosine, O-18 F-fluoroethyl-L-tyrosine, and 3-18 F-fluoro-a-methyl-L-tyrosine ( 18 F-FAMT) have already been introduced into clinical practice (1,3,4). However, their widespread application in clinical studies is limited by the short halflives of 11 C and 18 F. It may be possible to deliver an 18 F-labeled amino acid tracer as is done with 18 F-FDG, but the development of PET tracers using radionuclides with longer half-lives may constitute a way to circumvent the problem.Among the positron emission radionuclides, 76 Br has been proposed as an attractive candidate for using PET (decay mode: b 1 5 57%, electron capture 5 43%). 76 Br can be produced with a low-energy cyclotron by the nuclear reaction of 76 Se(p,n) 76 Br (5). The ...

Radiobrominated benzimidazole-quinoline derivatives as Platelet-derived growth factor receptor beta (PDGFRβ) imaging probes

“…Hanaoka et al . performed 77 Br labeling of α-methyl-phenylalanine by bromodestannylation reaction with NCS, and its radiochemical yield was approximately 60% 32 . In these reports, using the same corresponding precursors, the radiochemical yields for radiobromine labeling were lower than those for radioiodine labeling.…”

“…However, the biodistribution of free bromide ions is much different. Because the free bromide ions accumulate in blood and are retained for a long time 32 , 33 , the radioactivity in the blood can be used as an in vivo stability index for radiobromine-labeled compounds. As summarized in Tables 1 and 2 , [ 77 Br] 2 and [ 77 Br] 3 were stable in vivo because the blood clearances of both radiotracers were rapid.…”

The chemo- enzymatic synthesis of labeled l-amino acids and some of their derivatives

“…2′-[ 18 F]fluoro- l -Tyr is used for glioma imaging [145]. 2′-[ 76 Br]bromo-α-methyl- l -Phe is a potential PET tumor tracer [146]. 3′-[ 125 I]iodo-α-methyl- l -Tyr as well as 4′-[ 123 I]iodo- l -Phe are validated for visualization by SPECT [147, 148] and 5′-[ 18 F]fluoro-α-methyl- l -Trp holds great potential for cancer imaging using PET [149].…”

Improvement and Optimization of Clinically Potent Positron Emitter ⁷⁶Br Isolation Using the Dry Distillation Approach for its Future Automation

“…To reduce the amount of Se in the 76 Br solution, the target material should be heated repeatedly prior to use for irradiations. Clinical potent 76 Br-labeled compounds, 76 Br-MBBG, a PET tracer for norepinephrine-transporter expressing tumors [14] and 76 Br-labeled amino acid tracers for various kinds of cancer imaging [15,16] were successfully synthesized using 76 Br isolated by the new system. These results indicate that enough amounts of highly pure 76 Br for clinical applications is isolated by the improved system under optimized condition and can be useful for the synthesis of clinically potent PET tracers.…”