Radiosynthesis of carbon-11 labeled PDE5 inhibitors as new potential PET radiotracers for imaging of Alzheimer's disease

Abstract

To develop PET tracers for imaging of Alzheimer's disease, new carbon-11 labeled potent and selective PDE5 inhibitors have been synthesized. The reference standards (5) and (12), and their corresponding desmethylated precursors (6) and (13) were synthesized from methyl 2-amino-5bromobenzoate and (4-methoxyphenyl)methanamine in multiple steps with 2%, 1%, 1% and 0.2% overall chemical yield, respectively. The radiotracers ([ 11 C]5) and ([ 11 C]12) were prepared from their corresponding precursors 6 and 13 with [ 11 C]CH3OTf through O-11 C-methylation and isolated by HPLC combined with SPE in 40-50% radiochemical yield, based on [ 11 C]CO2 and decay corrected to EOB. The radiochemical purity was >99%, and the molar activity (Am) at EOB was in a range of 370-740 GBq/µmol.

Challenges on Cyclic Nucleotide Phosphodiesterases Imaging with Positron Emission Tomography: Novel Radioligands and (Pre-)Clinical Insights since 2016

“…Interestingly, highest radiochemical yields for automated radiosynthesis of [ 18 F]17 were achieved by using the nosylate precursor and [ 18 F]TBAF with the addition of small amounts of water to the reaction mixture [73]. 4) have been published by collaborating research groups from Hebei, China, and Indiana, USA [75,77]. Dong et al [75] focused on the PDE5 enzyme as a promising non-beta amyloid-related target for treatment and imaging of Alzheimer´s disease and thus, [ 11 C]19 and [ 11 C]20 were generated to investigate PDE5 in the brain by PET.…”

“…For that purpose, radioligands with subnanomolar potency and high target selectivity are required as mentioned above. Out of a series of novel naphthyridine and 1H-pyrroloquinolinone analogs [75,82], the most potent candidates 19 and 20 displayed picomolar inhibitory potency towards PDE5 and excellent selectivity over PDE6 (Figure 4), which shows high similarity in the catalytic site with PDE5 [82]. Besides, Xu et al [77] reported on the development of [ 11 C]21 for PET imaging of PDE5 in the heart.…”

“…In 4) have been published by collaborating research groups from Hebei, China, and Indiana, USA [75,77]. Dong et al [75] focused on the PDE5 enzyme as a promising non-beta amyloid-related target for treatment and imaging of Alzheimer's disease and thus, [ 11 C]19 and [ 11 C]20 were generated to investigate PDE5 in the brain by PET. For that purpose, radioligands with subnanomolar potency and high target selectivity are required as mentioned above.…”

“…In that regard, the novel radioligands [ 18 F]5 for PDE4B [55] and [ 11 C]13 for PDE4D [66] are currently the most promising candidates and under further investigation. Neuroimaging of PDE5 is challenging due to the low enzyme expression in the brain, but the radioligands [ 11 C]19 and [ 11 C]20 showed picomolar potency and excellent selectivity towards PDE5 [75] and thus, in vivo evaluation of these will certainly be followed with great attention. Besides, [ 18 F]16 is proposed as appropriate PDE5 radioligand for the examination of altered enzyme density in heart failure and for myocardial PDE5 occupancy studies [72].…”

On the Viability of Tadalafil-Based 18F-Radiotracers for In Vivo Phosphodiesterase 5 (PDE5) PET Imaging

“…The latest PDE5-targeting radiotracers, quinolines 10 and 11 , and 4(3 H )-pyrimidinone 12 , have been developed as high-potency PET tracers (IC 50 = 0.056, 0.059, 0.62 nM, respectively) for imaging PDE5 in AD and heart disease, although their use in animal or tissue studies has yet to be reported. 27 , 28 …”