[18F]DPA-714, [18F]PBR111 and [18F]FEDAA1106-selective radioligands for imaging TSPO 18 kDa with PET: automated radiosynthesis on a TRACERLAb FX-FN synthesizer and quality controls.

Imaging of TSPO 18 kDa with PET is more and more considered as a relevant biomarker of inflammation in numerous diseases. Development of new radiotracers for TSPO 18 kDa has seen acceleration in the last years and the challenge today is to make available large amounts of such a radiotracer in compliance with GMP standards for application in humans. We present in this technical note automated productions of [(18)F]DPA-714, [(18)F]PBR111 and [(18)F]FEDAA1106, three promising radiotracers for TSPO 18 kDa imaging, using a TRACERlab FX-FN synthesizer. This note also includes the quality control data of the validation batches for the manufacturing qualification of clinical production of [(18)F]DPA-714.

Kuhnast B ，Damont A ，Hinnen F ，Catarina T ，Demphel S ，Le Helleix S ，Coulon C ，Goutal S ，Gervais P ，Dollé F ... -  《-》

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.

Bourdier T ，Pham TQ ，Henderson D ，Jackson T ，Lam P ，Izard M ，Katsifis A ... -  《-》

[18F]DPA-C5yne, a novel fluorine-18-labelled analogue of DPA-714: radiosynthesis and preliminary evaluation as a radiotracer for imaging neuroinflammation with PET.

DPA-C5yne, the lead compound of a novel series of DPA-714 derivatives in which the fluoroethoxy chain linked to the phenylpyrazolopyrimidine scaffold has been replaced by a fluoroalkyn-1-yl moiety, is a high affinity (Ki : 0.35 nM) and selective ligand targeting the translocator protein 18 kDa. In the present work, DPA-C5yne was labelled with no-carrier-added [(18)F]fluoride based on a one-step tosyloxy-for-fluorine nucleophilic substitution reaction, purified by cartridge and HPLC, and formulated as an i.v. injectable solution using a TRACERLab FX N Pro synthesizer. Typically, 4.3-5.2 GBq of [(18)F]DPA-C5yne, ready-to-use, chemically and radiochemically pure (> 95%), was obtained with specific radioactivities ranging from 55 to 110 GBq/µmol within 50-60 min, starting from a 30 GBq [(18)F]fluoride batch (14-17%). LogP and LogD of [(18)F]DPA-C5yne were measured using the shake-flask method and values of 2.39 and 2.51 were found, respectively. Autoradiography studies performed on slices of ((R,S)-α-amino-3-hydroxy-5-methyl-4-isoxazolopropionique (AMPA)-lesioned rat brains showed a high target-to-background ratio (1.9 ± 0.3). Selectivity and specificity of the binding for the translocator protein was demonstrated using DPA-C5yne (unlabelled), PK11195 and Flumazenil (central benzodiazepine receptor ligand) as competitors. Furthermore, DPA-C5yne proved to be stable in plasma at 37°C for at least 90 min.

Médran-Navarrete V ，Bernards N ，Kuhnast B ，Damont A ，Pottier G ，Peyronneau MA ，Kassiou M ，Marguet F ，Puech F ，Boisgard R ，Dollé F ... -  《-》

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.

Hoareau R ，Shao X ，Henderson BD ，Scott PJ ... -  《-》

Synthesis and in vitro characterization of novel fluorinated derivatives of the translocator protein 18 kDa ligand CfO-DPA-714.

The translocator protein 18 kDa (TSPO) is today a validated target for a number of therapeutic applications, but also a well-recognized diagnostic/imaging biomarker for the evaluation of inflammatory related-disease state and progression, prompting the development of specific and dedicated TSPO ligands worldwide. For this purpose, pyrazolo[1,5-a]pyrimidine acetamides constitute a unique class of high affinity and selectivity TSPO ligands; it includes DPA-714, a fluorine-containing derivative that has also been labelled with the positron-emitter fluorine-18, and is nowadays widely used as a Positron Emission Tomography imaging probe. Recently, to prevent defluorination issues encountered in vivo with this tracer, a first series of analogues was reported where the oxygen atom bridging the phenyl ring of the core structure and the fluorinated moiety was replaced with a more robust linkage. Among this new series, CfO-DPA-714 was discovered as a highly promising TSPO ligand. Herein, a novel series of fluorinated analogues of the latter molecule were synthesized and in vitro characterized, where the pharmacomodulation at the amide position of the molecule was explored. Thirteen compounds were thus prepared from a common key-ester intermediate (synthesized in 7 steps from 4-iodobenzoate - 11% overall yield) and a set of commercially available amines and obtained with moderate to good yields (23-81%) and high purities (>95%). With one exception, all derivatives displayed nanomolar to subnanomolar affinity for the TSPO and also high selectivity versus the CBR (Ki (CBR)/Ki (TSPO) > 103). Within this series, three compounds showed better Ki values (0.25, 0.26 and 0.30 nM) than that of DPA-714 (0.91 nM) and CfO-DPA-714 (0.37 nM), and favorable lipophilicity for brain penetration (3.6 < logD7.4 < 4.4). Among these three compounds, the N-methyl-N-propyl amide analogue (9) exhibited similar metabolic stability when compared to CfO-DPA-714 in mouse, rat and human microsomes. Therefore, the latter compound stands out as a promising candidate for drug development or for use as a PET probe, once fluorine-18-labelled, for in vivo neuroinflammation imaging.

Cacheux F ，Médran-Navarrete V ，Dollé F ，Marguet F ，Puech F ，Damont A ... -  《-》