From Carbon-11-Labeled Amino Acids to Peptides in Positron Emission Tomography: the Synthesis and Clinical Application.

Radiolabeled amino acids, their derivatives and peptides have a broad scope of application and can be used as receptor ligands, as well as enzyme substrates for many different diseases as radiopharmaceutical tracers. Over the past few decades, the application of molecular imaging techniques such as positron emission tomography (PET) has gained considerable importance and significance in diagnosis in today's advanced health care. Next to that, the availability of cyclotrons and state-of-the-art radiochemistry facilities has progressed the production of imaging agents enabling the preparation of many versatile PET radiotracers. Due to many favorable characteristics of radiolabeled amino acids and peptides, they can be used for tumor staging and monitoring the progress of therapy success, while aromatic amino acids can be employed as PET tracer to study neurological disorders. This review provides a comprehensive overview of radiosynthetic and enzymatic approaches towards carbon-11 amino acids, their analogues and peptides, with focus on stereoselective reactions, and reflects upon their clinical application.

Radiosynthesis of 1-iodo-2-[11 C]methylpropane and 2-methyl-1-[11 C]propanol and its application for alkylation reactions and C-C bond formation.

The multitude of biologically active compounds requires the availability of a broad spectrum of radiolabeled synthons for the development of positron emission tomography (PET) tracers. The aim of this study was to synthesize 1-iodo-2-[11 C]methylpropane and 2-methyl-1-[11 C]propanol and investigate the use of these reagents in further radiosynthesis reactions. 2-Methyl-1-[11 C]propanol was obtained with an average radiochemical yield of 46 ± 6% d.c. and used with fluorobenzene as starting material. High conversion rates of 85 ± 4% d.c. could be observed with HPLC, but large precursor amounts (32 mg, 333 µmol) were needed. 1-Iodo-2-[11 C]methylpropane was synthesized with a radiochemical yield of 25 ± 7% d.c. and with a radiochemical purity of 78 ± 7% d.c. The labelling agent 1-iodo-2-[11 C]methylpropane was coupled to thiophenol, phenol and phenylmagnesium bromide. Average radiochemical conversions of 83% d.c. for thiophenol, 40% d.c. for phenol, and 60% d.c. for phenylmagnesium bromide were obtained. In addition, [11 C]2-methyl-1-propyl phenyl sulphide was isolated with a radiochemical yield of 5 ± 1% d.c. and a molar activity of 346 ± 113 GBq/µmol at the end of synthesis. Altogether, the syntheses of 1-iodo-2-[11 C]methylpropane and 2-methyl-1-[11 C]propanol were achieved and applied as proof of their applicability.

A rapid and highly enantioselective C-11C bond formation of l-[11C]phenylalanine via chiral phase-transfer catalysis.

A rapid method for the synthesis of carbon-11 radiolabeled phenylalanine was developed using a chiral phase-transfer catalyst and a sub-nanomolar quantity of [11C]benzyl iodide as a radio-precursor. Based on a reported synthesis of [11C]benzyl iodide, a Schiff base precursor was evaluated for stereoselective [11C]benzylation. Extensive and interactive screening of the precursor, catalyst, base, stirring and temperature was required to achieve high stereoinduction. The result is an efficient 5-step radiolabeling method to reliably synthesize l- or d-[11C]phenylalanine with an excellent enantiomeric excess of >90% and almost quantitative radiochemical conversion of >95% (n > 5). Additionally, a phase-transfer catalyzed alkylation was utilized on the preparative scale using automated platform. The application resulted in high specific activity ranging from 85-135 GBq µmol-1 of the enantiomerically pure [11C]phenylalanine, showing that the process is robust and amenable to broad use in PET.

Improved synthesis and application of [(11) C]benzyl iodide in positron emission tomography radiotracer production.

Positron emission tomography has increased the demand for new carbon-11 radiolabeled tracers and building blocks. A promising radiolabeling synthon is [(11) C]benzyl iodide ([(11) C]BnI), because the benzyl group is a widely present functionality in biologically active compounds. Unfortunately, synthesis of [(11) C]BnI has received little attention, resulting in limited application. Therefore, we investigated the synthesis in order to significantly improve, automate, and apply it for labeling of the dopamine D2 antagonist [(11) C]clebopride as a proof of concept. [(11) C]BnI was synthesized from [(11) C]CO2 via a Grignard reaction and purified prior the reaction with desbenzyl clebopride. According to a one-pot procedure, [(11) C]BnI was synthesized in 11 min from [(11) C]CO2 with high yield, purity, and specific activity, 52 ± 3% (end of the cyclotron bombardment), 95 ± 3%, and 123 ± 17 GBq/µmol (end of the synthesis), respectively. Changes in the [(11) C]BnI synthesis are reduced amounts of reagents, a lower temperature in the Grignard reaction, and the introduction of a solid-phase intermediate purification. [(11) C]Clebopride was synthesized within 28 min from [(11) C]CO2 in an isolated decay-corrected yield of 11 ± 3% (end of the cyclotron bombardment) with a purity of >98% and specific activity (SA) of 54 ± 4 GBq/µmol (n = 3) at the end of the synthesis. Conversion of [(11) C]BnI to product was 82 ± 11%. The reliable synthesis of [(11) C]BnI allows the broad application of this synthon in positron emission tomography radiopharmaceutical development.