Thomas Bourdier

Discovery of [18F]N-(2-(Diethylamino)ethyl)-6-fluoronicotinamide: A Melanoma Positron Emission Tomography Imaging Radiotracer with High Tumor to Body Contrast Ratio and Rapid Renal Clearance

The high melanoma uptake and rapid body clearance displayed by our series of [(123)I]iodonicotinamides prompted the development of [(18)F]N-(2-(diethylamino)ethyl)-6-fluoronicotinamide ([(18)F]2), a novel radiotracer for PET melanoma imaging. Significantly, unlike fluorobenzoates, [(18)F]fluorine incorporation on the nicotinamide ring is one step, facile, and high yielding. [(18)F]2 displayed high tumor uptake, rapid body clearance via predominantly renal excretion, and is currently being evaluated in preclinical studies for progression into clinical trials to assess the responsiveness of therapeutic agents.

Radiosynthesis and Biological Evaluation of l- and d-S-(3-[18F]Fluoropropyl)homocysteine for Tumor Imaging Using Positron Emission Tomography

Interest in radiolabeled amino acids for metabolic imaging of cancer and limitations with [(11)C]methionine has prompted the development of a new (18)F-labeled methionine derivative S-(3-[(18)F]fluoropropyl)homocysteine ([(18)F]FPHCys). The L and D enantiomers of [(18)F]FPHCys were prepared from their respective protected S-(3-tosyloxypropyl)homocysteine precursors 1 by [(18)F]fluoride substitution using K(2.2.2) and potassium oxalate, followed by acid hydrolysis on a Tracerlab FX(FN) synthesis module. [(18)F]-L-FPHCys and [(18)F]-D-FPHCys were isolated in 20 ± 5% radiochemical yield and >98% radiochemical and enantiomeric purity in 65 min. Competitive uptake studies in A375 and HT29 tumor cells suggest that L- and D-[(18)F]FPHCys are taken up by the L-transporter system. [(18)F]-L-FPHCys and [(18)F]-D-FPHCys displayed good stability In Vivo without incorporation into protein at least 2 h postinjection. Biodistribution studies demonstrate good uptake in A375 tumor-bearing rodents with tumor to blood ratios of 3.5 and 5.0 for [(18)F]-L-FPHCys and [(18)F]-D-FPHCys, respectively, at 2 h postinjection.

Automated radiosynthesis of [18F]PBR111 and [18F]PBR102 using the Tracerlab FXFN and Tracerlab MXFDG module for imaging the peripheral benzodiazepine receptor with PET.

[(18)F]PBR111 and [(18)F]PBR102 are selective radioligands for imaging of the Peripheral Benzodiazepine Receptor (PBR). We have developed a fully automated method for the radiosynthesis of [(18)F]PBR111 and [(18)F]PBR102 in the Tracerlab FX(FN) (30±2% radiochemical yield non-decay-corrected for both tracers) and Tracerlab MX(FDG) (25±2% radiochemical yield non-decay-corrected for both tracers) from the corresponding p-toluenesulfonyl precursors. For all tracers, radiochemical purity was >99% and specific activity was >150GBq/μmol after less than 60min of preparation time.

Synthesis and Radiosynthesis of a Novel PET Fluorobenzyl Piperazine for Melanoma Tumour Imaging; [18F]MEL054

2-{2-[4-(4-[18F]-Fluorobenzyl)piperazin-1-yl]-2-oxoethyl}isoindolin-1-one ([18F]MEL054), is a new potent indolinone-based melanin binder designed to target melanotic tumours. [18F]MEL054 was prepared by an automated two-step radiosynthesis, comprising of the preparation of 4-[18F]fluorobenzaldehyde from 4-formyl-N,N,N-trimethylanilinium triflate, followed by reductive alkylation with 2-(2-oxo-2-piperazin-1-ylethyl)isoindolin-1-one. 4-[18F]Fluorobenzaldehyde was prepared on a GE TRACERlab FXFN module in 68 ± 8 % radiochemical yield (RCY, non-decay corrected), purified by a Sep-Pak Plus C18 cartridge and eluted into the reactor of an in-house modified Nuclear Interface [18F]FDG synthesis module for the subsequent reductive alkylation reaction. HPLC purification produced [18F]MEL054 in a collected RCY of 34 ± 9 % (non-decay corrected), the total preparation time (including Sep-Pak Plus C18 and HPLC purification) did not exceed 105 min. The radiochemical purity of [18F]MEL054 was greater than 99 % with a specific radioactivity of 71–119 GBq μmol–1 and [18F]MEL054 remained stable in saline solution (>98 %) after 3 h.

Preclinical characterization of 18F-D-FPHCys, a new amino acid-based PET tracer

PurposeThe imaging potential of a new 18F-labelled methionine derivative, S-(3-[18F]fluoropropyl)-d-homocysteine (18F-D-FPHCys), and its selectivity for amino acid transporter subtypes were investigated in vitro and by imaging of human tumour xenografts.MethodsExpression of members of the system L (LAT isoforms 1–4 and 4F2hc) and ASCT (ASCT isoforms 1 and 2) amino acid transporter subclasses were assessed by quantitative real-time PCR in four human tumour models, including A431 squamous cell carcinoma, PC3 prostate cancer, and Colo 205 and HT-29 colorectal cancer lines. The first investigations for the characterization of 18F-D-FPHCys were in vitro uptake studies by comparing it with [1-14C]-l-methionine (14C-MET) and in vivo by PET imaging. In addition, the specific involvement of LAT1 transporters in 18F-D-FPHCys accumulation was tested by silencing LAT1 mRNA transcription with siRNAs. To determine the proliferative activity in tumour xenografts ex vivo, Ki-67 staining was used as a biomarker.ResultsA431 cells showed the highest 18F-D-FPHCys uptake in vitro and in vivo followed by Colo 205, PC3 and HT-29. A similar pattern of retention was observed with 14C-MET. 18F-D-FPHCys retention was strongly correlated with LAT1 expression both in vitro (R2 = 0.85) and in vivo (R2 = 0.99). Downregulation of LAT1 by siRNA inhibited 18F-D-FPHCys uptake, demonstrating a clear dependence on this transporter for tumour uptake. Furthermore, 18F-D-FPHCys accumulation mirrored cellular proliferation.ConclusionThe favourable properties of 18F-D-FPHCys make this tracer a promising imaging probe for detection of tumours as well as for the noninvasive evaluation and monitoring of tumour growth.

Synthesis of [11C]PBR170, a novel imidazopyridine, for imaging the translocator protein with PET

The translocator protein (TSPO) ligand 2-(6,8-dichloro-2-(4-ethoxyphenyl)imidazo[1,2-a]pyridin-3-yl)-N-(2-fluoropyridin-3-yl)-N-methylacetamide (PBR170), is a novel imidazopyridineacetamide with high affinity (2.6 nm) and selectivity for the TSPO. The synthesis of [(11)C]PBR170 was accomplished by N-methylation of the corresponding desmethyl precursor with [(11)C]methyl iodide in the presence of sodium hydroxide in dimethylformamide. [(11)C]PBR170 was produced in 30-45% radiochemical yield (decay-corrected, based on [(11)C]methyl iodide) with a radiochemical purity >98% and a specific activity of 90-190 GBq/μmol after 35 min of synthesis time.