Synthesis, Radiolabeling, and Biological Evaluation of the cis Stereoisomers of 1-Amino-3-Fluoro-4-(fluoro-¹⁸F)Cyclopentane-1-Carboxylic Acid as PET Imaging Agents

Abstract

The non-natural cyclic amino acids (1S,3R,4S)-1-amino-3-fluoro-4-(fluoro-18 F)­cyclopentane-1-carboxylic acid ([18F]­9) and (1S,3S,4R)-1-amino-3-fluoro-4-(fluoro-18 F)­cyclopentane-1-carboxylic acid ([18F]­28) have been prepared in 10 and 1.7% decay corrected radiochemical yield, respectively, and in greater than 99% radiochemical purity. Cell assays in rat 9L gliosarcoma, human U87 ΔEGFR glioblastoma, and human DU145 androgen-independent prostate carcinoma tumor cells indicated that both compounds are substrates for amino acid transport primarily by system L, with some transport taking place via system ASC. In rats with 9L gliosarcoma, [18F]­9 and [18F]­28 provided high tumor to normal brain tissue ratios, with maximal ratios of 3.5 and 4.1, respectively. Biodistribution studies in healthy rats confirmed that both compounds are BBB permeable and that bladder accumulation is low until at least 5 min post injection.

Synthesis, Radiolabeling, and Biological Evaluation of the trans-Stereoisomers of 1-Amino-3-(fluoro-18F)-4-fluorocyclopentane-1-carboxylic Acid as PET Imaging Agents

“…The target compound, racemic trans -3,4-DFACPC ( 5 ), was prepared in four steps starting from racemic triflate 1 (Scheme ), which was obtained as previously described . Briefly, compound 1 underwent a clean S N 2 inversion hydrolysis with aqueous NaHCO 3 to give racemic fluorohydrin 2 in nearly quantitative yield.…”

“…Racemic trans -3,4-[ 18 F]-DFACPC ( [ 18 F]­5 ) was prepared as previously described for the synthesis of anti - cis -3,4-[ 18 F]-DFACPC, except that in the fluorination reaction, [ 18 F]­CsF was employed instead of [ 18 F]­KF to overcome the problem of elimination, as described in the cold chemistry. The method involves a one-pot, two-step reaction sequence consisting of nucleophilic fluorination of the corresponding triflate precursor 3 with [ 18 F]­CsF in 1:1 t butanol/acetonitrile with Kryptofix 222 for 10 min, followed by cleavage of the protecting groups using 6 M HCl (Scheme ).…”

“…Competitive uptake inhibition experiments of [ 18 F]­5 were accomplished under the conditions previously reported for cis -difluoro stereoisomers . Cell uptake of [ 18 F]­5 was evaluated in the presence and absence of inhibitors in the following cell lines: rat 9L gliosarcoma, human U87 ΔEGFR glioblastoma, and human DU145 androgen-independent prostate carcinoma.…”

“…The preparation of racemic [ 18 F]­5 was based on the previously reported automated synthesis of anti-cis -3,4-[ 18 F]-DFACPC . To a glass vessel containing a solution of Cryptand 222 in MeCN (22 mg/mL) (1.0 mL) was added 1460 mCi of no-carrier-added [ 18 F]­HF through a trap/release (T/R) cartridge by using a solution of Cs 2 CO 3 /H 2 O (20 mg mg/mL) (0.6 mL).…”

Stereodivergent Synthesis of Carbocyclic Quaternary α‐Amino Acid Derivatives Containing Two Contiguous Stereocenters

“…Carbocyclic quaternary α‐amino acid derivatives are an important class of non‐natural amino acid derivatives, which are key structural fragments in numerous drug candidates and natural products possessing extraordinary biological activities (Scheme 1a). [ 1 ] These compounds have been increasingly incorporated into modified peptides, which displayed special conformation, improved activity, enhanced stability and pharmacokinetic properties compared with their natural counterparts. [ 2 ] In addition, they were also employed as versatile precursors for the privileged chiral ligands/catalysts in asymmetric synthesis.…”