Evaluation of [¹¹C]N-Methyl Lansoprazole as a Radiopharmaceutical for PET Imaging of Tau Neurofibrillary Tangles

Abstract

[(11)C]N-Methyl lansoprazole ([(11)C]NML, 3) was synthesized and evaluated as a radiopharmaceutical for quantifying tau neurofibrillary tangle (NFT) burden using positron emission tomography (PET) imaging. [(11)C]NML was synthesized from commercially available lansoprazole in 4.6% radiochemical yield (noncorrected RCY, based upon [(11)C]MeI), 99% radiochemical purity, and 16095 Ci/mmol specific activity (n = 5). Log P was determined to be 2.18. A lack of brain uptake in rodent microPET imaging revealed [(11)C]NML to be a substrate for the rodent permeability-glycoprotein 1 (PGP) transporter, but this could be overcome by pretreating with cyclosporin A to block the PGP. Contrastingly, [(11)C]NML was not found to be a substrate for the primate PGP, and microPET imaging in rhesus revealed [(11)C]NML uptake in the healthy primate brain of ∼1600 nCi/cc maximum at 3 min followed by rapid egress to 500 nCi/cc. Comparative autoradiography between wild-type rats and transgenic rats expressing human tau (hTau +/+) revealed 12% higher uptake of [(11)C]NML in the cortex of brains expressing human tau. Further autoradiography with tau positive brain samples from progressive supranuclear palsy (PSP) patients revealed colocalization of [(11)C]NML with tau NFTs identified using modified Bielschowsky staining. Finally, saturation binding experiments with heparin-induced tau confirmed K d and Bmax values of [(11)C]NML as 700 pM and 0.214 fmol/μg, respectively.

Molecular Imaging Insights into Neurodegeneration: Focus on Tau PET Radiotracers

“…11 C-N-methyl lansoprazole is the 11 C-labeled version of the Food and Drug Administration-approved drug lansoprazole and appears to have an exceptionally high affinity for tau (8). However, to the best of our knowledge no human data have been published with this radiotracer yet.…”

Synthesis and evaluation of [11C]PyrATP-1, a novel radiotracer for PET imaging of glycogen synthase kinase-3β (GSK-3β)

“…Given that Pgp transporter expression is significantly higher in rodents than primates [26], and that we have previously seen species differences in brain uptake of radiotracers because of this [16], we chose to also evaluate [ 11 C]PyrATP-1 in rhesus macaque (n = 1). However in this case, the lack of brain uptake was found to be interspecific, and no brain uptake was apparent from the primate scan either (Figure 3c).…”

“…Dysfunction of this process is thought to generate the hyperphosphorylated tau that aggregates into tau neurofibrillary tangles in Alzheimer’s disease [6, 15], and is aligned with our program developing radiotracers for PET imaging of tau [16]. In our search for a radiotracer that would enable PET imaging of GSK-3β, we were particularly attracted by a recent report of a family of pyrazines (e.g.…”

Radiosyntheses using Fluorine-18: The Art and Science of Late Stage Fluorination

“…For example, at its simplest, biodistribution studies with radiolabeled versions of drug candidates can be used to non-invasively determine whether or not a molecule reaches the target tissue in vivo in rodents and primates initially, and eventually in humans. For example, this approach can be used in the development of CNS drugs to evaluate whether or not a candidate molecule crosses the blood-brain-barrier [254]. Data obtained from such experiments can also provide a wealth of other important information, such as whether or not a drug candidate also accumulates at non-target sites with potential to cause side effects or dose-limiting toxicity at intended therapeutic doses.…”