Synthesis and evaluation of [¹¹C]PBD150, a radiolabeled glutaminyl cyclase inhibitor for the potential detection of Alzheimer's disease prior to amyloid β aggregation

Abstract

The phenol of 1-(3-(1H-imidazol-1-yl)propyl)-3-(4-hydroxy-3-methoxyphenyl)thiourea was selectively carbon-11 labelled to generate [11C]PBD150 in 7.3% yield from [11C]methyl triflate (non-decay corrected; radiochemical purity ≥95%, specific activity = 5.7 Ci/µmol, n=5). Evaluation of [11C]PBD150 by small animal PET imaging (mouse and rat) determined it does not permeate the blood brain barrier, indicating previously described therapeutic effect in transgenic mice was likely not the result of inhibiting central nervous system glutaminyl cyclase.

Synthesis and Evaluation of [18F]RAGER: A First Generation Small-Molecule PET Radioligand Targeting the Receptor for Advanced Glycation Endproducts

“…1 H NMR spectra were obtained at 400 MHz on Varian NMR spectrometer in CD 3 OD or d 6 -DMSO solutions at room temperature with tetramethylsilane (TMS, δ = 0) as an internal standard. 13 C NMR spectra were obtained at 100 MHz, and 19 F-NMR spectra were obtained at 376 MHz. Chemical shifts (δ) are reported in ppm, and coupling constants are reported in hertz.…”

“…When this gap in knowledge is considered along with the immense socioeconomic burden of AD, , the urgent need for a series of PET radioligands to better understand the entire pathway of AD progression and support AD therapeutic development efforts is apparent (for recent perspectives on other potential imaging targets in AD, see refs and ). To this end, our laboratory and others have been working extensively to develop PET probes relevant to AD outside the scope of traditional Aβ targeting, such as radioligands with affinity for metal–Aβ species, , glutaminyl-cyclase, and glycogen synthase kinase-3 . Notably, we are increasingly interested in using PET to understand mechanisms underlying the increased accumulation of amyloid in the central nervous system (CNS) in AD.…”

In vitroandin silicodetermination of glutaminyl cyclase inhibitors

“…In general, 1_x series and reference compound 1 are in of the rule of CNS drugs, conrmed their estimations in BBB penetration below. However, PDB150, a 1 derivative, was demonstrated to impossible permeation the BBB, 28 indicating the same result of 1 on BBB penetration study. Therefore, log(BBB) was employed for more BBB information.…”

“…2B). 28 Aer these considerations, we designed the new hQC inhibitory series without urea and thiourea scaffolds. In the rst series, thiourea groups were replaced by a bioisostere or a fused heterocyclic ring.…”

Teaching old molecules new tricks: repurposing investigational drugs as chemical probes

“…These findings are consistent with reports that pharmacological doses of certain CNS drugs exhibit higher brain uptake than microdoses 136 and, in addition to MCC950, there are other instances of drugs with demonstrable CNS effects at therapeutic doses subsequently failing to enter the brain when adapted into PET radiotracers. 137,138 This is an important concept that is becoming more apparent and should be kept in mind as the application of PET imaging in CNS drug development continues to increase. Several aspects of this proposed mechanism are not clear.…”