IC‐P‐069: First in man study to image alpha4beta2 cerebral nicotinic acetylcholine receptors (nAChRs) in early Alzheimer's disease (AD) with the new radioligand (‐)‐[18F]‐norchloro‐fluoro‐homoepibatidine (NCFHEB) and PET

(−)‐[18F]Flubatine: evaluation in rhesus monkeys and a report of the first fully automated radiosynthesis validated for clinical use

“…Uptake was normalized to injected dose and averaged for the three scans (Figure ). Higher uptake and slower washout of (−)‐[ 18 F]flubatine were observed in the thalamus than those in the other regions of the brain, which was expected and is consistent with previously reported data in piglets and humans . Peak uptake for the thalamus in the rhesus monkeys (45 min) was found to be faster than the reported peak uptake for piglets (80 min).…”

“…Peak uptake for the thalamus in the rhesus monkeys (45 min) was found to be faster than the reported peak uptake for piglets (80 min). Although no obvious explanation exists for this species difference, it does lend support to the recent suggestion that (−)‐[ 18 F]flubatine kinetics will allow all kinetic parameters to be estimated from clinical PET data acquired over only 90 min . Finally, the injection of a 2.5‐µg/kg dose of the selective α 4 β 2 nAChR agonist nifene at 60 min initiated a slow washout of [ 18 F]flubatine from the thalamus, with about 25% clearance by the end of the imaging study at 90 min (Figure ).…”

“…Final purification by semi‐preparative HPLC involved an initial chiral column to separate enantiomers and then a second HPLC to remove chemical impurities and provide (−)‐[ 18 F]flubatine in 2% yield . This chemistry has proven suitable for the initial preclinical evaluation of the radiopharmaceutical and the first‐in‐man evaluation that has been recently reported . However, as we looked to make (−)‐[ 18 F]flubatine available to our clinicians, we had cause to develop an entirely new synthesis more suitable for our synthesis equipment, by using the newly commercially available enantiomerically pure Boc‐protected trimethylammonium salt precursor.…”

“…With the goal of expanding our understanding of cholinergic dysfunction in our clinical population, we were desirous of also making a radiopharmaceutical available for clinical imaging of nAChRs. Many radiopharmaceuticals for quantification of nAChRs have been reported to date (reviewed in Refs 2–7), but we focused our attention on [ 18 F]A85380 and [ 18 F]flubatine ([ 18 F]NCFHEB) as they have been used to image nAChRs in a clinical setting. Ultimately, [ 18 F]flubatine, a radiolabeled derivative of epibatidine, was selected because it has the most practical kinetic profile (the slow kinetics of [ 18 F]A85380 severely limit its utility for imaging cognitively impaired patients).…”

Evaluation of the sensitivity of the novel α4β2* nicotinic acetylcholine receptor PET radioligand 18F‐(‐)‐NCFHEB to increases in synaptic acetylcholine levels in rhesus monkeys

“…In the past few years, several other radioligands have been developed in order to find a more suitable tracer allowing shorter studies. To date, two such radioligands have been tested in humans: 18 F‐(‐)‐NCFHEB (also known as 18 F‐(‐)‐Flubatine) (Sabri et al, ) and 18 F‐AZAN (Wong et al, ). Both tracers were reported to have faster kinetics than previous compounds and to allow quantification of α4β2*‐nAChRs in humans with scan durations of less than 2 h. The goal of this study was to investigate whether 18 F‐(‐)‐NCFHEB is also suitable to measure increases in acetylcholine concentration following administration of acetylcholinesterase inhibitors.…”