Development of a new F-18-labelled quinoline derivative as PET neuroimaging probe for PDE5

Aim:

Cyclic nucleotide phosphodiesterase 5 (PDE5) is an enzyme that regulates the intracellular levels of the second messenger cyclic guanosine monophosphate (cGMP). Within the CNS, PDE5 is highly expressed in the cerebellum and the hippocampus. There is currently a growing interest in using inhibitors of PDE5 such as Sildenafil (Viagra®) as possible drug for treatment of cognitive impairment in Alzheimer’s and Huntington’s Disease. Moreover, effects of PDE5 inhibitors on the growth of different tumour cells are reported. Therefore we aimed to develop a F-18-labelled radioligand for imaging of this enzyme particularly in brain.

Methods:

Based on a quinoline scaffold (1) a series of fluorinated derivatives was synthesized and their inhibitory activity for several PDEs was determined. F-18-labelling of the most promising candidate ICF24075* was performed by using a nosylate precursor. In vitro autoradiography of [18F]ICF24075 was performed on pig brain slices. In vivo metabolism was investigated in plasma and brain samples of mice at 30 min p.i. using micellar chromatography.
* 4-((3-chloro-4-methoxybenzyl)amino)-8-(3-(fluoro)azetidin-1-yl)-3-(hydroxymethyl)quinoline-6-carbonitrile

Results:

The inhibitory activity of ICF24075 toward PDE5 was determined with an IC50 value of 5.9 nM. F-18-labelling of the secondary carbon atom proceeded only with low labelling yields of around 7% resulting in RCY of 2%. In vitro binding studies demonstrated a specific blockade with sildenafil which was highest in the cerebellum. In vivo studies in mice revealed the formation of radiometabolites able to cross the blood-brain barrier.

Conclusions:

Due to the presence of radiometabolites in the brain, [18F]ICF24075 is not suitable for specific neuroimaging of PDE5. The unexpected fast metabolic degradation of the F-18-substituted azetidine ring is currently investigated by in vitro studies to confirm our assumption of N-dealkylation.