Synthesis and preliminary biological evaluation of S-11C-methyl-d-cysteine as a new amino acid PET tracer for cancer imaging

Abstract

S-(11)C-methyl-L-cysteine (LMCYS) is an attractive amino acid tracer for clinical tumor positron emission tomography (PET) imaging. D-isomers of some radiolabeled amino acids are potential PET tracers for tumor imaging. In this work, S-(11)C-methyl-D-cysteine (DMCYS), a D-amino acid isomer of S-(11)C-methyl-cysteine for tumor imaging was developed and evaluated. DMCYS was prepared by (11)C-methylation of the precursor D-cysteine, with an uncorrected radiochemical yield over 50 % from (11)CH3I within a total synthesis time from (11)CO2 about 12 min. In vitro competitive inhibition studies showed that DMCYS uptake was primarily transported through the Na(+)-independent system L, and also the Na(+)-dependent system B(0,+) and system ASC, with almost no system A. In vitro incorporation experiments indicated that almost no protein incorporation was found in Hepa 1-6 hepatoma cell lines. Biodistribution studies demonstrated higher uptake of DMCYS in pancreas and liver at 5 min post-injection, relatively lower uptake in brain and muscle, and faster radioactivity clearance from most tissues than those of L-isomer during the entire observation time. In the PET imaging of S180 fibrosarcoma-bearing mice and turpentine-induced inflammatory model mice, 2-(18)F-fluoro-2-deoxy-D-glucose (FDG) exhibited significantly high accumulation in both tumor and inflammatory lesion with low tumor-to-inflammation ratio of 1.40, and LMCYS showed low tumor-to-inflammation ratio of 1.64 at 60 min post-injection. By contrast, DMCYS showed moderate accumulation in tumor and very low uptake in inflammatory lesion, leading to relatively higher tumor-to-inflammation ratio of 2.25 than (11)C-methyl-L-methionine (MET) (1.85) at 60 min post-injection. Also, PET images of orthotopic transplanted glioma models demonstrated that low uptake of DMCYS in normal brain tissue and high uptake in brain glioma tissue were observed. The results suggest that DMCYS is a little better than the corresponding L-isomers as a potential PET tumor-detecting agent and is superior to MET and FDG in the differentiation of tumor from inflammation.

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

“…Labeled branched-chain natural AAs with unchanged structure are rare, for example (S-[ 11 C]methyl)-L-methionine ( 11 C-MET). Most labeled branched-chain natural AAs are changed into different structure labeled AAs from natural AAs, such as 18 F-FET, 2- 18 F-fluoro-L-tyrosine (2-FTYR), 6- 18 F-L-m-tyrosine ( 18 F-FMT), O-(3- 18 F-fluoropropyl)-L-tyrosine ( 18 F-FPT), 2- 18 F-L-phenylalanine, cis- 18 F-fluoroproline (cis-Fpro), (4S)-4-(3- 18 F-fluoropropyl)-L-glutamate (BAY 94-9392, 18 F-FSPG), (2S,4R)-4- 18 F-L-glutamate (BAY85-8050, 4F-GLU), L-(5- 11 C)-glutamine, (2S,4R)-4- 18 F-L-glutamine ( 18 F-(2 S ,4 R )4F-GLN), (2S,4S)-4-(3- 18 F-fluoropropyl) glutamine ( 18 F-FPGln), and (S- 11 C-methyl)-L-cysteine ( 11 C-MCYS) (Deng et al, 2011 ; Huang et al, 2015 ). Labeled branched-chain non-natural AAs include labeled branched-chain D-AAs and labeled branched-chain L-non-natural AAs.…”

“…Labeled branched-chain non-natural AAs include labeled branched-chain D-AAs and labeled branched-chain L-non-natural AAs. The former includes D- 11 C-fluoromethyltyrosine, D- 18 F-fluoromethyltyrosine ( 18 F-D-FMT) (Burger et al, 2014 ) and (S- 11 C-methyl)-D-cysteine ( 11 C-DMCYS) (Huang et al, 2015 ). The latter includes 3- 18 F-α-methyltyrosine ( 18 F-FAMT), 1-amino-3- 18 F-fluorocyclobutane-1-carboxylic acid ( 18 F-FACBC), 3- O -methyl-6- 18 F-L-3, 4-dihydroxyphenylalanine ( 18 F-OMFD), (S)-2-amino-3-[1-(2- 18 F-fluoroethyl)-1H-[1,2,3]triazol-4-yl]propanoic acid ( 18 F-AFETP), 3- 18 F-2-methyl-2-(methylamino)propanoic acid ( 18 F-MeFAMP), 3,4-dihydroxy-6- 18 F-L-phenylalanine ( 18 F-FDOPA), anti-1-amino-2- 18 F-fluorocyclopentane-1-carboxylic acid (anti-2- 18 F-FACPC), 5- 18 F-L-aminosuberic acid ( 18 F-FASu), 11 C-HTP, L-[β- 11 C]DOPA ( 11 C-DOPA), L-[β- 11 C] dopamine, and 18 F-fluoropropyl-L-tryptophan ( 18 F-FPTP) (Jager et al, 2001 ; McConathy and Goodman, 2008 ; McConathy et al, 2012 ; He et al, 2013 ; Huang and McConathy, 2013b ; Webster et al, 2014 ).…”

“…Moreover, there is not yet enough evidence about grading glioma, and its use in differentiating tumor recurrences from radiation necrosis is controversial (Ishii et al, 1993 ; 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 PET-imaging tracer (Figure 3 ) (Deng et al, 2011 ; Huang et al, 2015 ).…”

Synthesis of enantiopure 18F-trifluoromethyl cysteine as a structure-mimetic amino acid tracer for glioma imaging

“…To address these deficiencies, S- [ 11 C]-methyl-L-cysteine 1L ( S -[ 11 C]CH 3 -L-CYS) and S- [ 11 C]-methyl-D-cysteine 1D ( S -[ 11 C]CH 3 -D-CYS), a pair of 11 C-labelled S -methylcysteine enantiomers ( Figure 1A and Figure S1B ), were successively developed via 11 C-isotopic substitution in our previous studies 35-38. Preliminary studies indicated that the tracers were superior to [ 18 F]FDG and [ 11 C]MET in the differentiation of tumor from inflammation 35, 36, 38-40. Nevertheless, the short half-life of 11 C ( t 1/2 = 20.4 min) restricts the widespread application of these tracers, resulting in an urgent demand for 18 F-labelled SAA tracers ( 18 F, t 1/2 = 109.8 min).…”

Radiolabeling and Preclinical Evaluation of a New S-Alkylated Cysteine Derivative Conjugated to C-Substituted Macrocycle for Positron Emission Tomography

“… 29 Deng et al and Huang et al also reported the synthesis of S-alkylated cysteine derivatives, with high uptake in the tumor and nearly no accumulation in the protein components. 26 , 27 Therefore an S-alkylated amino acid derivative PET imaging agent with a chelator, shown to possess high stability with metal ions in the M 2+ and M 3+ form, especially Ga(III), was proposed. ATRIDAT, already reported by our group to form thermodynamically stable and strong complexes with Ga(III) was used for conjugating the cysteine derivative after slight modification in the pendant arm, keeping the macrocyclic framework intact.…”