Carbon-11 and Fluorine-18 Labeled Amino Acid Tracers for Positron Emission Tomography Imaging of Tumors

Tumor cells have an increased nutritional demand for amino acids (AAs) to satisfy their rapid proliferation. Positron-emitting nuclide labeled AAs are interesting probes and are of great importance for imaging tumors using positron emission tomography (PET). Carbon-11 and fluorine-18 labeled AAs include the [1-11C] AAs, labeling alpha-C- AAs, the branched-chain of AAs and N-substituted carbon-11 labeled AAs. These tracers target protein synthesis or amino acid (AA) transport, and their uptake mechanism mainly involves AA transport. AA PET tracers have been widely used in clinical settings to image brain tumors, neuroendocrine tumors, prostate cancer, breast cancer, non-small cell lung cancer (NSCLC) and hepatocellular carcinoma. This review focuses on the fundamental concepts and the uptake mechanism of AAs, AA PET tracers and their clinical applications.

is high. Thus, images with adequate contrast can be obtained using AA PET tracers for primary and metastatic brain tumors. Also, some AA PET tracers have an advantage over  in the differentiation of tumor from inflammation (Rau et al., 2002;Tang et al., 2003;Stober et al., 2006). It was reported that O-(2-18 F-fluoroethyl)-L-tyrosine ( 18 F-FET) and (S-11 C-methyl)-L-methionine ( 11 C-MET) have a significantly higher uptake in tumor cells than that in inflammatory cells. This different appearance can be contributed to major AAs transporter system L (Stober et al., 2006). They can also differentiate recurrent brain tumors from pseudo-progression or radiation necrosis among patients after surgery and radiotherapy (Niyazi et al., 2012;Galldiks et al., 2015a,b). In addition, some AA PET tracers with relatively little renal excretion can accurately detect prostate cancer and show high specificity and sensitivity, superior to 18 F-FDG (Toth et al., 2005;Jana and Blaufox, 2006). Last, 18 F-FDG is a nonspecific substrate for neuroendocrine tumors, but a few AA PET tracers are substrates of the enzyme aromatic AA decarboxylase (AADC), which are specific for neuroendocrine tumors imaging, such as 3,4-dihydroxy-6-18 Ffluoro-L-phenylalanine ( 18 F-FDOPA) and 5-hydroxy-L-[β-11 C] tryptophan ( 11 C-HTP) (Jager et al., 2008;Oberg and Castellano, 2011). This review focuses on the fundamental concepts of AAs and the uptake mechanism of AAs, AA PET tracers and their clinical applications.

FUNDAMENTAL CONCEPTS AND UPTAKE MECHANISMS OF AAS
L-AAs, as essential small-molecule nutrient substances, are crucial for maintaining cell growth and nitrogen balance. Their biological functions are involved in metabolism, protein synthesis, cell signaling transduction, regulating gene expression. They are also precursors for the synthesis of hormones, neurotransmitter, and nitrogenous substances. L-AAs are commonly found in proteins and are either obtained from intracellular protein recycling or are transported into the cell from the extracellular surroundings (Stryer, 1995).
The transporters mediate AA transport across plasma membranes in mammals and are divided into several "systems." The systems present various transporting mechanisms, including dependence on sodium and independence on sodium, tissue expression patterns, substrate specificity and sensitivity to pH or hormones (Utsunomiya-Tate et al., 1996;Castagna et al., 1997). Cells possess different transport systems in their plasma membranes, consisting of generally existed transport systems (such as systems A, ASC, L, y + and X AG − , X C − ), and tissue-specific transport systems (such as systems B 0 , and b 0,+ ) (Palacin et al., 1998). Here, we focus on describing their general features and transport mechanism of AAs, as shown in Table 1 and Figure 1.
System A is Na + -dependent transporter for serving mainly small aliphatic AAs, such as serine, alanine, and glutamine. It is a member of the solute carrier 38 (SLC38) gene family. Three subtypes of system A have been isolated: sodium-coupled neutral AA transporter 1 (SNAT1), 2, and 4. SNAT 3 and 5 belong to the system N (glutamine preferring) AA transport family, which is also a member of the SLC38 gene family (Broer, 2014). System A and system N are all directly concentrative and function essentially with a monodirectional efflux. System A transports AAs with the N-methyl group and N-methyl aminoisobutyric acid (MeAIB) is a specific inhibitor that can inhibit system A transport activity due to competitive saturation effects. Meanwhile, the activity of transporters is affected by many factors (Shotwell et al., 1983). The activity of system A is sensitive to pH alterations, highly down-regulated by acidic extracellular surroundings, and up-regulated by glucagon, insulin, and growth factors (Castagna et al., 1997).
The ASC system is Na + -dependent exchanger capable of mediating net influx or efflux, with substrates (L-alanine, L-serine, L-cysteine, and L-glutamine) and a member of solute the carrier family 1(SLC1) (Castagna et al., 1997). Two subtypes have been isolated: ASC-Type AA transporter 1 (ASCT1) and ASC-Type AA transporter 2 (ASCT2). ASCT2 utilizes an intracellular gradient of AAs, efflux of intracellular AAs in exchange for extracellular AAs. Glutamine is a key substrate of ASCT2 with important roles in tumor metabolism (Fuchs et al., 2007). ASCT2 is over-expressed in many human tumor cell lines including hepatocellular carcinoma, prostate, breast, glioma, and colon tumor cell lines (Li et al., 2003;Fuchs and Bode, 2005). L-γ-glutamyl-p-nitroanilide (GPNA) is used as a specific inhibitor of ASCT2 transporter activity (Schulte et al., 2015). The activity of system ASC is pH-insensitive within a range of pH 5.65-8.2 (Fuchs and Bode, 2005;Kanai et al., 2013).
The Na + -independent system L is the major route that takes up branched and aromatic AAs from the extracellular space, such as phenylalanine, isoleucine, tryptophan, valine, methionine and histidine (Castagna et al., 1997). Four subtypes of system L have been isolated: L-type AA transporters 1 (LAT1), LAT2, LAT3, and LAT4. LAT1 and LAT2 are members of the SLC7 gene family, while LAT3 and LAT4 are members of the SLC43 gene family. LAT1 and LAT2 possess "4F2 light chains" containing 12 putative membrane-spanning domains, which covalently bind a type-II membrane glycoprotein heavy chain (4F2hc) with disulfide bridges to produce a functional heterodimeric transporter. LAT3 and LAT4, without 4F2hc, facilitate the transport of AAs (Fuchs and Bode, 2005;Aiko et al., 2014). System L plays an important role for AAs crossing the placenta barrier and the blood-brain barrier (Christensen, 1990). 2-amino-2-norbornane-carboxylic acid (BCH) is a specific inhibitor for system L transporter activity (Palacin et al., 1998;Babu et al., 2003).
The cationic AA transporters include systems B 0,+ , y + , and y + L, and the anionic AA transporters contain systems X AG − and X C − . Systems B, B 0 , B 0,+ y + , and y + L are related Na + -dependent transporter systems. They mediate the absorption of branchedchain, aliphatic and aromatic AAs. Systems B and B 0 are tissuespecific transport systems and present in renal proximal tubular and intestinal epithelial brush-border membranes. Both systems are more broadly specific for neutral AAs than systems A and ASC. System y + transporters are members of the SLC7 gene family. Four subtypes, CAT-1, CAT-2 (A and B), CAT-3, and Frontiers in Chemistry | www.frontiersin.org FIGURE 1 | A principle scheme of the metabolic pathways and substrates accounting for the intracellular uptake of key clinical amino acids PET tracers for imaging tumor metabolism. Positron nuclide-labeled amino acids are shown in red colored words. AA, amino acid; ASCT, L-alanine, L-serine, cysteine transporter; ASCT2, ASC-type amino acid transporter 2 (SLC1A5); Gln, glutamine; Glu, glutamate; LAT1, L-type amino acid transporter 1 (SLC7A5); SNAT, system A amino acid transporter; EAAT, Excitatory amino acid transporters; xCT, a light chain of anionic amino acid transporter system X C − (SLC7A11); TCA, tricarboxylic acid cycle.
CAT-4, have been recognized from a subfamily of the SLC7 gene family. CAT-1 is a exchanger targeting unessential AAs, and the action of CAT-4 remains unknown (Hammermann et al., 2001). System y + transports cationic AAs and some neutral AAs, such as lysine and arginine, resulting in electrogenic transport (Castagna et al., 1997;Palacin et al., 1998). System y + L transporters are members of the SLC7 gene family as well. Two subtypes (y + LAT1 and y + LAT2) have been identified, and they create heterodimers with the 4F2hc glycoprotein to be functional AA transporters, such as the LAT1 and LAT2 transporters from system L. System y + L serves large neutral and cationic AAs with an exchange mechanism. ATB 0,+ belongs to the SLC6 gene family and serves cationic and neutral AAs in the presence of sodium and chloride. b 0,+ AT belongs to the SLC7 gene family, which constitutes a functional heterodimer with the glycoprotein D2/rBAT/NBAT and serves cationic and neutral AAs via an exchange mechanism in the absence of sodium (Torrents et al., 1998;Hammermann et al., 2001). System X C − is Na + -independent and Cl − -dependent heterodimeric AA transporter (Baker et al., 2002;Lewerenz et al., 2012Lewerenz et al., , 2013, an obligate, electroneutral, cysteine/glutamate antiporter, exchanges extracellular cystine for intracellular glutamate (Lo et al., 2008;Lewerenz et al., 2012). It is composed of a subunit xCT light chain and a subunit 4F2 heavy chain (4F2hc). xCT is a member of SLC7, member 11 (SLC7A11), and phosphorylation of xCT can modulate the activity of system X C − (Baker et al., 2002;Lo et al., 2008;Lewerenz et al., 2012). It is not only a potential target for therapy but also a potential PET biomarker for imaging the system X C − activity of cancer and other diseases (Lo et al., 2008;Reissner and Kalivas, 2010;Koglin et al., 2011).
The transporter systems mentioned above are the main targets for AA metabolism PET imaging of tumors (Jager et al., 2001). Tumor cells utilize more AAs compared with normal cells to satisfy their rapid proliferation and invasion demands. And studies indicated that the expression of AA transporters is higher in tumor cells than that in normal tissue, especially LAT1, ASCT2, xCT, and ATB 0,+ and so on (Karunakaran et al., 2011;Toyoda et al., 2014;Schulte et al., 2015). Both ASCT2 and LAT1 are upregulated three-fold in the most of cancerous tissues. LAT1 has been proven to be associated with tumor growth (Kaira et al., 2013), for example 11 C-MET, 18 F-FET, and 18 F-FDOPA are the most widely used AA PET tracers for imaging brain tumors. System A and cationic or anionic AA transporters are overexpressed in dividing cells in certain human cancers (Bussolati et al., 1996). Many examples are showed in Table 2. Tumor cell accumulation of AA PET tracers mainly depends on the rate and mechanism of AAs transport. Based on the over-expression of AA transporters, the uptake of AA PET tracers in tumor cells is greater than that in normal cells (Mossine et al., 2016).

AA PET TRACERS
Most AA PET tracers are labeled with positron radionuclides 11 C and 18 F. Theoretically, almost all AAs be labeled with 11 C, however, their short half-life (20 min, 100% of beta positron decay) is not suitable for delayed PET imaging. To overcome this shortcoming of 11 C and to facilitate the utility of AA PET tracers in hospitals without on-site cyclotron and labeling equipment, a series of 18 F labeled AAs (half-life of 110 min, 97% of beta positron decay) were developed (Mossine et al., 2016). Based on that AAs have a common molecular formula [R-CH-(NH 2 )-COOH], with a carboxylic acid group (-COOH), an amino group (-NH 2 ) linking to the alpha-carbon atom (-CH-), and branched-chain group (-R). Thus, 11 C and 18 F labeled AAs are divided into [1-11 C] AAs ([1-11 C]AAs), alpha-C labeled AAs (alpha-C labeled AAs), labeled branched-chain AAs (branched-chain AAs), and N-substituted labeled AAs (N-substituted labeled AAs), which include natural and nonnatural AAs.
Labeled natural AAs associated with structure-changed and structure-unchanged labeled AAs. Structure-unchanged labeled natural AAs, such as [1-11 C] AAs and 11 C-Met, do not chemically change the structure of AAs and can maintain the prototype structure and the fundamental pharmacodynamics and pharmacokinetics characteristics of AAs. So, they are mainly incorporated into protein synthesis, with minor AA transport. On the contrary, structure-changed labeled AAs (such as 18 F-FET, (S-11 C-methyl)-L-cysteine) do chemically change the structure of AAs, which are slightly incorporated into protein synthesis. Like structure-changed labeled AAs, labeled non-natural AAs (such as 18 F-FDOPA, 11 C-HTP) are mainly involved into AA transport. Most important 11 C-and 18 F-labeled AA tracers are shown in Table 2.

CLINICAL APPLICATIONS
AA PET tracers were first used to measure the rate of protein synthesis in vivo (Vaalburg et al., 1992;Ishiwata et al., 1993;Paans et al., 1996). For example, 11 C-labeled natural AAs, such as L-leucine, L-methionine, L-phenylalanine and L-tyrosine, are used to measure the protein synthesis rate since they incorporate into proteins or wash out with decarboxylation and oxidation (Ishiwata et al., 1996;Langen et al., 2006). Nowadays, AA transports seem to be more important than protein synthesis for the imaging of tumor metabolism in vivo Lewis et al., 2015). A wide range of 11 C and 18 F AAs have been developed as PET tracers for clinical tumor imaging, as shown in Table 2 and Figure 2. The established AA tracers are used for imaging of brain tumors, neuroendocrine tumors, and prostate cancer, and other tumors.

Brain Tumor
Though 18 F-FDG has been used in PET imaging of brain tumors, there exists weaknesses as mentioned (Olivero et al., 1995;Suchorska et al., 2014;Zhao et al., 2014;Tomura et al., 2015). AA PET tracers can overcome its limitations and provide a better description of tumor boundaries, which is important for surgical interventions, targeting biopsies, and radiation therapy (Suchorska et al., 2014). And 18 F-FDG has been replaced by AA PET tracers or its analogs in clinical settings. The most widely used AA PET tracers are 11 C-MET, 18 F-FET, and 18 F-FDOPA (Gulyas and Halldin, 2012;Wang et al., 2014).   Compared to 18 F-FDG, the superior diagnostic accuracy of 11 C-MET has been demonstrated in detecting, grading, delineating and searching recurrences, prediction of prognosis and evaluation of response to treatment (Nariai et al., 2005;Van Laere et al., 2005;Ceyssens et al., 2006;Galldiks et al., 2006). However, the sensitivity of 11 C-MET was lower in the studies with high proportions of low-grade glioma (Hatakeyama et al., 2008;Glaudemans et al., 2013), which is the most universal type of primary brain tumor. Moreover, there is not yet enough evidence about grading glioma, and its use in differentiating tumor recurrences from radiation necrosis is controversial Sonoda et al., 1998;Nakagawa et al., 2002;Tsuyuguchi et al., 2004;Minamimoto et al., 2015). 11 C-MCYS, a new AA PET tracer for tumor imaging, is reported that it, as analog of 11 C-MET, appeared to have potential value as a tumor PETimaging tracer (Figure 3) (Deng et al., 2011;Huang et al., 2015). 18 F-FET and 18 F-FDOPA are derivatives of 18 F-labeled Lphenylalanine and L-tyrosine, which target system L transporters to detect brain tumors. 18 F-FET provides both good-contrast PET images of brain tumors (Figure 4) (Langen et al., 2006;Lau et al., 2010;Dunet et al., 2012) and valuable information about differentiating low-grade from high-grade tumor (Popperl et al., 2007;Dunet et al., 2012;Jansen et al., 2015). Dynamic 18 F-FET examinations show high diagnostic accuracy in patients with suspected tumor progression or recurrence in clinical settings (Lau et al., 2010;Dunet et al., 2012). 18 F-FET also can differentiate recurrent brain tumor from pseudoprogression and radiation necrosis (Niyazi et al., 2012;Galldiks et al., 2015a,b). Additionally, 18 F-FET has a lower uptake by inflammatory cells than 11 C-MET or 18 F-FDG and it clearly delineates tumors from inflammation (Gulyas and Halldin, 2012;Nedergaard et al., 2014). 18 F-FDOPA is an analog of L-dopa, and 18 F-OMFD is a major metabolite of 18 F-FDOPA (Beuthien-Baumann et al., 2003;Gulyas and Halldin, 2012). 18 F-FDOPA has been used to investigate the activity of aromatic L-AA decarboxylase and to evaluate the dopaminergic system functioning in brain tumors and neuroendocrine tumors. 18 F-FDOPA has been used for detecting primary, metastatic and recurrent brain tumors, and provides valuable information on the delineation of tumor volume, the determination of proliferative activities and grading ( Figure 5) (Chen et al., 2006;Fueger et al., 2010;Pafundi et al., 2013;Juhász et al., 2014). The uptake of 18 F-FDOPA correlates with the glioma grade, thus it plays an important role for managing patients in clinical settings (Fueger et al., 2010;Walter et al., 2012;Pafundi et al., 2013).

Neuroendocrine Tumors
Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms from cells of the endocrine and nervous systems. Identifying the accurate location of primary tumors and metastases are essential for the treatment of NETs. 18 F-FDG is a nonspecific tracer for NETs, and its uptake is always low in well-differentiated NETs (Huang and McConathy, 2013b).
Knowledge about NETs uptake amine precursors led to the development of 11 C-HTP and 18 F-FDOPA. 11 C-HTP is useful for detecting small tumors and early recurrences, however, the 20-min half-life of 11 C limits the wide clinical use of 11 C-HTP (Oberg and Castellano, 2011;Toumpanakis et al., 2014).
NETs increase activity of L-DOPA decarboxylase, so they show a high accumulation of 18 FDOPA (Jager et al., 2008). 18 F-FDOPA is a favorable AA tracer for diagnosing NETs with high accuracy, such as pheochromocytomas (Figure 6) (Wong et al., 2011), pancreatic pheochromocytoma and insulinomas, and for staging carcinoids (Koopmans et al., 2006;Timmers et al., 2007;Huang and McConathy, 2013b). Additionally, 18 F-FDOPA is a highly sensitive marker in patients with functional carcinoid tumors and has low sensitivity for malignant NETs, such as medullary thyroid cancer and pancreatic islet cell tumors (Weisbrod et al., 2012).

Prostate Cancers
Prostate cancer is a complex and biologically heterogeneous tumor, which is the second leading cause of cancer-related death in the United States and Europe (Huang and McConathy, 2013b). 18 F-FDG is not an adequate tracer for differentiating prostate cancer, benign hyperplasia lesion and normal prostate (Picchio et al., 2015), and it is not useful for initial staging and is of limited utility in the clinical setting of biochemical failure after prior definitive therapy for primary cancer (Jadvar, 2016). 11 C-MET is a helpful tracer for imaging the prostate in patients with increased PSA levels (Toth et al., 2005;Jana and Blaufox, 2006). Short dynamic scanning limits the wide clinical use of 11 C-MET for imaging prostate cancer. 18 F-FACBC, an L-leucine analog, is a valuable tracer in the assessment of prostate cancer. Due to its low urinary excretion after injection (Figure 7), it has advantages in the imaging of prostate cancer (Schuster et al., 2007  McConathy, 2013b; Picchio et al., 2015). Prostate cancer, within the prostate or in pelvic lymph node metastases, can be detected using 18 F-FACBC with high sensitivity and specificity Castellucci and Jadvar, 2012). The vitro uptake studies demonstrate that 18 F-FACBC is transported by LAT1 and ASCT2 in prostate cancer cell lines (Oka et al., 2012). More studies are needed to evaluate this radiotracer in the clinical management of men with prostate cancer . 18 F-FACPC, as an analog of 18 F-FACBC, is a helpful tracer for imaging prostate cancer, but 18 F-FACPC is not a good tracer for imaging pelvic lymph node metastases compared to 18 F-FACBC (Savir-Baruch et al., 2011).

Other Tumors
In maxillofacial tumors, the sensitivity of 18 F-FAMT is higher than that of 18 F-FDG, demonstrating that the accurate diagnosis of maxillofacial tumors is possible with 18 F-FAMT (Miyakubo et al., 2007).
Head and neck cancer can be imaged with 11 C-MeAIB. 11 C-MeAIB shows active and rapid transport into tumor tissues and salivary glands (Sutinen et al., 2003). 11 C-MeAIB is also helpful in the differential diagnosis of pulmonary and mediastinal mass lesions (Nishii et al., 2013). 18 F-D-FMT (BAY 86-9596), a derivative of 18 F-labeled tyrosine and is transported via the system L transporter 1 (LAT-1), showed a lower sensitivity but higher specificity for 18 F-D-FMT than 18 F-FDG in patients with NSCLC and head and neck squamous cell cancer and (Burger et al., 2014). 4-borono-2-18 F-fluoro-phenylalanine ( 18 F-FBPA) was developed to predict 10 B concentrations, presumably after administration of boron-containing drug for neutron-capture therapy (BNCT) (Wang et al., 2004;Menichetti et al., 2009;Tani et al., 2014). Studies showed that 18 F-FBPA, was transported by system L, could evaluate BPA uptake in tumors for screening candidates for BNCT (Havu-Auren et al., 2007;Menichetti et al., 2009;Yoshimoto et al., 2013). However, the inconsistent result was showed that 18 F-FDG might be an effective tracer prior to 18 F-FBPA for screening patients with head and neck cancer for treatment with BNCT (Tani et al., 2014;Kobayashi et al., 2016).

CONCLUSION AND PROSPECTS
AA PET tracers can overcome the shortcomings of 18 F-FDG and provide more information for imaging tumors. Uptake mechanism of AA PET tracers involves protein synthesis or AA transport. For PET imaging, AA transport tracers appear more valuable than protein synthesis tracers in clinical applications. Targeting AA transporter system A, ASC, L and X C − , have been used in the clinical imaging of the biological behaviors of various tumors. Transporter system L has been a major focus of tracer development for imaging tumors (such as 11 C-MET, 18 F-FET, 18 F-FDOPA) and has also led to several AA tracers that are effective for imaging neuroendocrine tumors ( 18 F-FDOPA) and prostate cancer ( 18 F-FACBC) (Huang and McConathy, 2013a). , which is specific for system X C − transporters (Koglin et al., 2011;Smolarz et al., 2013a), has been used for imaging patients with hepatocellular carcinoma (Baek et al., 2013), NSCLC (Smolarz et al., 2013a) and breast cancer (Chopra, 2004;Baek et al., 2012). Recently, new 18 F-labeled branched-chain AAs have been developed that target cationic AA transporter and excitatory AA transporters X AG − , which are potential targets of AA PET tracers for tumor imaging. O-2((2-[(18)F]fluoroethyl)methylamino)ethyltyrosine ( 18 F-FMAET) is specific for cationic AA transporter (Chiotellis et al., 2014). BAY 85-8050, a glutamate derivative, is specific for transport system X C − and systems X AG − , which is used to study healthy volunteers (Krasikova et al., 2011;Ploessl et al., 2012).
Besides branched-chain AAs, novel N-substituted labeled AAs and AA mimetics, have also been developed. 18 F-FPGLU is Nmethylsubstitutebeled amino glutamic acid as a potential AA tracer for PET imaging of transporter X AG − and X C − in tumor, and can be used for clinical tumor imaging in the near future. 18 F-Phe-BF 3 (an exotic replacement of the carboxylate with -BF 3 ) is a new class of AA mimetics-boramino acid tracer for PET imaging of transporter LAT1 in tumor, with specific accumulation in U87MG xenografts and low uptake in normal brain and an inflammatory region (Liu et al., 2015). Also, synthesis of novel AAs with conformationally constrained side chains will lead to developing a series of new radiolabeled AA mimetics for imaging disease, with good prospect (Mollica et al., 2010(Mollica et al., , 2012Stefanucci et al., 2011;Way et al., 2014).
Novel radiolabeling techniques are developing for radiosynthesis of AA PET tracers, resulting in routine high-dose production of AA tracers for clinical PET imaging. Recently, the no-carrier-added (NCA) enantioselective synthesis using a chiral phase-transfer catalyst has been used for automated synthesis of NCA 18 F-FDOPA with the Curie Level (Libert et al., 2013), and simple and efficient two-step synthesis of 18 F-FDOPA with short synthesis times can supply adequate radioactivity for clinical imaging (Tredwell et al., 2014). Thus, 18 F-FDOPA is easily available and will become widely used AA PET tracer for the detection of brain tumors, neuroendocrine tumors, Parkinson's disease (PD), and mental illness (Darcourt et al., 2014;Eggers et al., 2014;Li et al., 2014). Simple and practical click reaction and 68 Ga labeling methods are also used for preparing new AA tracers for imaging tumors, which will further boost translational application of AA tracers in clinics.

AUTHOR CONTRIBUTIONS
GT is the corresponding author for summarize amino acids PET tracers and the future about amino acids PET. He also reviewed this paper. AS searched literature and wrote the manuscript. XL searched literature and drew the figure and table.