Bradford D. Henderson

Automated production of [11C]acetate and [11C]palmitate using a modified GE Tracerlab FXC-Pro

As researchers explore new applications for positron emission tomography radiopharmaceuticals, the demand for effective and readily available radiopharmaceuticals continues to increase. The syntheses of two such radiopharmaceuticals, [(11)C]acetate and [(11)C]palmitate, can be automated on the GE Tracerlab FX(C-Pro) by utilizing Grignard reactions. Radiochemical purities of the [(11)C]acetate and the [(11)C]palmitate products were high (>98% and >99.9%, respectively) with average non-corrected yields of 18% (n = 3) and 10% (n = 5), respectively. These data comprise the validation trials for site qualification of clinical production of both radiopharmaceuticals.

A fully-automated one-pot synthesis of [18F]fluoromethylcholine with reduced dimethylaminoethanol contamination via [18F]fluoromethyl tosylate.

INTRODUCTION A novel one-pot method for preparing [(18)F]fluoromethylcholine ([(18)F]FCH) via in situ generation of [(18)F]fluoromethyl tosylate ([(18)F]FCH2OTs), and subsequent [(18)F]fluoromethylation of dimethylaminoethanol (DMAE), has been developed. METHODS [(18)F]FCH was prepared using a GE TRACERlab FXFN, although the method should be readily adaptable to any other fluorine-(18) synthesis module. Initially ditosylmethane was fluorinated to generate [(18)F]FCH2OTs. DMAE was then added and the reaction was heated at 120 °C for 10 min to generate [(18)F]FCH. After this time, reaction solvent was evaporated, and the crude reaction mixture was purified by solid-phase extraction using C(18)-Plus and CM-Light Sep-Pak cartridges to provide [(18)F]FCH formulated in USP saline. The formulated product was passed through a 0.22 µm filter into a sterile dose vial, and submitted for quality control testing. Total synthesis time was 1.25 h from end-of-bombardment. RESULTS Typical non-decay-corrected yields of [(18)F]FCH prepared using this method were 91 mCi (7% non-decay corrected based upon ~1.3 Ci [(18)F]fluoride), and doses passed all other quality control (QC) tests. CONCLUSION A one-pot liquid-phase synthesis of [(18)F]FCH has been developed. Doses contain extremely low levels of residual DMAE (31.6 µg/10 mL dose or ~3 ppm) and passed all other requisite QC testing, confirming their suitability for use in clinical imaging studies.

Fully automated radiosynthesis of [11C]PBR28, a radiopharmaceutical for the translocator protein (TSPO) 18 kDa, using a GE TRACERlab FXC-Pro

In order to image the translocator protein (TSPO) 18kDa in the clinic using positron emission tomography (PET) imaging, we had a cause to prepare [(11)C]PBR28. In this communication we highlight our novel, recently developed, one-pot synthesis of the desmethyl-PBR28 precursor, as well as present an optimized fully automated preparation of [(11)C]PBR28 using a GE TRACERlab FX(C-Pro). Following radiolabelling, purification is achieved by HPLC and, to the best of our knowledge, the first reported example of reconstituting [(11)C]PBR28 into ethanolic saline using solid-phase extraction (SPE). This procedure is operationally simple, and provides high quality doses of [(11)C]PBR28 suitable for use in clinical PET imaging studies. Typical radiochemical yield using the optimized method is 3.6% yield (EOS, n=3), radiochemical and chemical purity are consistently >99%, and specific activities are 14,523Ci/mmol.

An updated synthesis of [11C]carfentanil for positron emission tomography (PET) imaging of the μ-opioid receptor

[11 C]Carfentanil ([11 C]CFN) is a selective radiotracer for in vivo positron emission tomography imaging studies of the μ-opioid system that, in our laboratories, is synthesized by methylation of the corresponding carboxylate precursor with [11 C]MeOTf, and purified using a C2 solid-phase extraction cartridge. Changes in the commercial availability of common C2 cartridges have necessitated future proofing the synthesis of [11 C]CFN to maintain reliable delivery of the radiotracer for clinical imaging studies. An updated synthesis of [11 C]CFN is reported that replaces a now obsolete purification cartridge with a new commercially available version and also substitutes the organic solvents used in traditional production methods with ethanol.

Development of Positron Emission Tomography (PET) Radiotracers for the GABA Transporter 1 (GAT-1)

In vivo positron emission tomography (PET) imaging of the γ-aminobutyric acid (GABA) receptor complex has been accomplished using radiolabeled benzodiazepine derivatives, but development of specific presynaptic radioligands targeting the neuronal membrane GABA transporter type 1 (GAT-1) has been less successful. The availability of new structure-activity studies of GAT-1 inhibitors and the introduction of a GAT-1 inhibitor (tiagabine, Gabatril) into clinical use prompted us to reinvestigate the syntheses of PET ligands for this transporter. Initial synthesis and rodent PET studies of N-[11C]methylnipecotic acid confirmed the low brain uptake of that small and polar molecule. The common design approach to improve blood-brain barrier permeability of GAT-1 inhibitors is the attachment of a large lipophilic substituent. We selected an unsymmetrical bis-aromatic residue attached to the ring nitrogen by a vinyl ether spacer from a series recently reported by Wanner and coworkers. Nucleophilic aromatic substitution of an aryl chloride precursor with [18F]fluoride was used to prepare the desired candidate radiotracer ( R, E/ Z)-1-(2-((4-fluoro-2-(4-[18F]fluorobenzoyl)styryl)oxy)ethyl)piperidine-3-carboxylic acid (( R, E/ Z)-[18F]10). PET studies in rats showed no brain uptake, which was not altered by pretreatment of animals with the P-glycoprotein inhibitor cyclosporine A, indicating efflux by Pgp was not responsible. Subsequent PET imaging studies of ( R, E/ Z)-[18F]10 in rhesus monkey brain showed very low brain uptake. Finally, to test if the free carboxylic acid group was the likely cause of poor brain uptake, PET studies were done using the ethyl ester derivative of ( R, E/ Z)-[18F]10. Rapid and significant monkey brain uptake of the ester was observed, followed by a slow washout over 90 min. The blood-brain barrier permeability of the ester supports a hypothesis that the free acid function limits brain uptake of nipecotic acid-based GAT-1 radioligands, and future radiotracer efforts should investigate the use of carboxylic acid bioisosteres.