Radiosynthesis and Biological Evaluation of N-[18F]Labeled Glutamic Acid as a Tumor Metabolic Imaging Tracer

Abstract

We have previously reported that N-(2-[18F]fluoropropionyl)-L-methionine ([18F]FPMET) selectively accumulates in tumors. However, due to the poor pharmacokinetics of [18F]FPMET in vivo, the potential clinical translation of this observation is hampered. In this study, we rationally designed and synthesized [18F] or [11C]labeled N-position L-glutamic acid analogues for tumor imaging. N-(2-[18F]fluoropropionyl)-L-glutamic acid ([18F]FPGLU) was synthesized with a 30±10% (n = 10, decay-corrected) overall radiochemical yield and a specific activity of 40±25 GBq/μmol (n = 10) after 130 min of radiosynthesis. In vitro cell experiments showed that [18F]FPGLU was primarily transported through the XAG – system and was not incorporated into protein. [18F]FPGLU was stable in urine, tumor tissues, and blood. We were able to use [18F]FPGLU in PET imaging and obtained high tumor to background ratios when visualizing tumors tissues in animal models.

Radiosynthesis and preliminary biological evaluation of N-(2-[18F]fluoropropionyl)-L-glutamine as a PET tracer for tumor imaging

“…The biodistribution of [ 18 F]FPGLN in normal mice was similar to [ 18 F]labeled glutamic acid analogue [ 18 F]FPGLU [11], both with radioactivity rapidly accumulated in kidneys and quickly excreted through the urinary-bladder route. A moderate uptake of radioactivity was shown in the liver, which is an important site of glutamine metabolism.…”

“…The uptake experiments showed that the transport characteristics of [ 18 F]FPGLN in SPC-A-1 cells was partly similar to that of [ 18 F]FPGLU, which was mediated through system X AG − , ASC, and Na-independent system L, with X AG − playing a dominant role [11]. The transport of [ 18 F]FPGLN was also partly similar to that of [ 18 F](2S,4R)4-fluoroglutamine, whose transport involved systems L, ASC, and N [13].…”

“…The radiosynthesis of [ 18 F]FPGLN via a two-step reaction sequence from 4-nitrophenyl-2-[ 18 F]fluoropropionate ([ 18 F]NFP) was similar to that of N -(2-[ 18 F]-fluoropropionyl)-L-glutamate [ 18 F]FPGLU described recently [11]. The fully automated synthesis of 4-nitrophenyl-2-[ 18 F]fluoropropionate ([ 18 F]NFP) was carried out on the PET-MF-2V-IT-I synthesizer via a simplified three step, one-pot procedure has been described in detail by the earlier paper [10].…”

“…Normal Kunming mice (female, 4-6 weeks old, 20-25g) for biodistrubution studies of [ 18 F]FPGLN and BALB/c nude mice (4-6 weeks old, 18-22g) for tumor-bearing models were obtained from Laboratory Animal Center of Sun Yat-Sen University (Guangzhou, China). The SPC-A-1 and PC-3 tumor-bearing models were made using the previously described methods [11, 23]. Tumor cells (1-2×10 7 ) were injected subcutaneously on left shoulder flank and allowed to grow for 2 to 3 weeks.…”

“…Although avid [ 18 F]FPMET uptake was seen on S180 fibrosarcoma, A549 lung adenocarcinoma and PC-3 prostate cancer xenografts, its potential use in a clinical study was hampered by poor stability and a high background signal in vivo . Recently, a N -[ 18 F]labeled L-glutamic acid analogue, N -(2-[ 18 F]fluoropropionyl)-L-glutamate ([ 18 F]FPGLU) was successfully synthesized as a potential novel PET tracer for glutamate metabolic imaging by our research group, which showed good tumor-to-background contrast in S180 fibrosarcoma, SPC-A-1 and LTEP-a-2 human lung adenocarcinoma mice models [11]. The objective of the present work was to radiosynthesize N -(2-[ 18 F]fluoropropionyl)-L-glutamine ([ 18 F]FPGLN), as shown in Figure 1, and to evaluate the potential value of this new PET imaging agent in vitro as well as in tumor-bearing nude mice models.…”