Automated preparation of the dopamine D2/3 receptor agonist ligand [11C]-(+)-PHNO for human PET imaging studies.

Carbon-11 labelled (+)-4-Propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol ([(11)C]-(+)-PHNO) is used as a high-affinity state, dopamine D(2/3) receptor ligand in clinical PET studies. To facilitate its use, robust, rapid, efficient and GMP compliant methods are required for the manufacturing and QC testing processes. Additionally, to allow for full quantification of the resulting signal in the CNS, a reliable method is required to establish the parent plasma concentration over the course of the scan. This paper provides high-quality methods to support clinical application of [(11)C]-(+)-PHNO.

Plisson C ，Huiban M ，Pampols-Maso S ，Singleton G ，Hill SP ，Passchier J ... -  《-》

Radiosynthesis and evaluation of [11C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol as a potential radiotracer for in vivo imaging of the dopamine D2 high-affinity state with positron emission tomography.

Wilson AA ，McCormick P ，Kapur S ，Willeit M ，Garcia A ，Hussey D ，Houle S ，Seeman P ，Ginovart N ... -  《JOURNAL OF MEDICINAL CHEMISTRY》

Radiosynthesis of the D2/3 agonist [3-11C]-(+)-PHNO using [11C]iodomethane.

We report here a radiosynthesis for the D(2/3) agonist (+)-4-([3-(11)C]propyl)-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol (3-[(11)C]-(+)-PHNO) labelled at the terminal carbon of the N-propyl chain. The protocol is based on (11)C-methylation of an N-acetyl precursor. This initial step is followed by a reduction with LiAlH(4) to give ([3-(11)C]-(+)-PHNO). We first applied the method for the synthesis of a model compound, N-3-([(11)C]propyl)-1,2,3,4-tetrahydroisoquinoline, which we obtained in 77-97% analytical radiochemical yield (n=6) in 20 min. Similarly, we prepared ([3-(11)C]-(+)-PHNO) in 55-60% analytical radiochemical yield (n=5) using a one-pot procedure. We have also been able to implement the complete process on a semi-automated module. This platform delivered purified and formulated [3-(11)C]PHNO with an average radiochemical yield of 9% (n=13, range 2-30%, non-decay corrected), a radiochemical purity >95%, and a specific radioactivity of 26.8-81.1 GBq/μmol in a total time of 63-65 min.

Francisco Garcia-Arguello S ，Fortt R ，Steel CJ ，Brickute D ，Glaser M ，Turton DR ，Robins EG ，Arstad E ，Luthra SK ... -  《-》

Dopamine D2 receptor radiotracers [(11)C](+)-PHNO and [(3)H]raclopride are indistinguishably inhibited by D2 agonists and antagonists ex vivo.

McCormick PN ，Kapur S ，Seeman P ，Wilson AA ... -  《-》

Syntheses and in vitro evaluation of fluorinated naphthoxazines as dopamine D2/D3 receptor agonists: radiosynthesis, ex vivo biodistribution and autoradiography of [(18)F]F-PHNO.

Vasdev N ，Seeman P ，Garcia A ，Stableford WT ，Nobrega JN ，Houle S ，Wilson AA ... -  《NUCLEAR MEDICINE AND BIOLOGY》