Radiosynthesis and Radiotracer Properties of a 7-(2-[18F]Fluoroethoxy)-6-methoxypyrrolidinylquinazoline for Imaging of Phosphodiesterase 10A with PET

Abstract

Phosphodiesterase 10A (PDE10A) is a key enzyme of intracellular signal transduction which is involved in the regulation of neurotransmission. The molecular imaging of PDE10A by PET is expected to allow a better understanding of physiological and pathological processes related to PDE10A expression and function in the brain. The aim of this study was to develop a new 18F-labeled PDE10A ligand based on a 6,7-dimethoxy-4-pyrrolidinylquinazoline and to evaluate its properties in biodistribution studies. Nucleophilic substitution of the 7-tosyloxy-analogue led to the 7-[18F]fluoroethoxy-derivative [18F]IV with radiochemical yields of 25% ± 9% (n = 9), high radiochemical purity of ≥99% and specific activities of 110–1,100 GBq/μmol. [18F]IV showed moderate PDE10A affinity (KD,PDE10A = 14 nM) and high metabolic stability in the brain of female CD-1 mice, wherein the radioligand entered rapidly with a peak uptake of 2.3% ID/g in striatum at 5 min p.i. However, ex vivo autoradiographic and in vivo blocking studies revealed no target specific accumulation and demonstrated [18F]IV to be inapplicable for imaging PDE10A with PET.

Synthesis, 18F-Radiolabelling and Biological Characterization of Novel Fluoroalkylated Triazine Derivatives for in Vivo Imaging of Phosphodiesterase 2A in Brain via Positron Emission Tomography

“…The IC50 values obtained by this assay represent relative measures of the respective target affinity of the compounds. We have previously shown for a specific PDE10A radioligand that the target affinity is within the same order of magnitude as the inhibitory potency of the corresponding non-radioactive reference compound [41].…”

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

“…High metabolic stability of the ether bond is expected because negligible defluorination was observed [178] . By contrast, [ 18 F]fl uoroacetamides have proven to be metabolically unstable due to hydrolytic cleavage [169] .…”

“…A further path to 18 We have recently used 18 F-labeled alkyltosylates for the radiolabeling of phenolic precursors via etherification to obtain high-affinity and selective radiotracers for the serotonin transporter [177] and the enzyme phosphodiesterase 10A [178] , respectively, with RCYs between 11% and 25%. High metabolic stability of the ether bond is expected because negligible defluorination was observed [178] .…”

Phosphodiesterase 10A inhibitors: a 2009 – 2012 patent update

“…MicroPET studies of [ 11 C]-MP-10 68 in monkeys displayed selective uptake in striatum, however, a radiolabeled metabolite capable of penetrating the blood--brain barrier may limit the clinical utility of [ 11 C]MP-10 as a PDE10A PET tracer. A [ 18 F]-ethyl derivative of the Pfizer compound PQ-10, 69 was developed as a potential PET ligand, however, in vivo blocking studies revealed no target-specific accumulation and demonstrated it to be inapplicable for imaging PDE10A with PET [92].…”