Fasoracetam

Fasoracetam ((5R)-5-(piperidine-1-carbonyl)pyrrolidin-2-one) is a synthetic racetam, built like piracetam on a 2-pyrrolidinone ring (PubChem CID 198695). Nippon Shinyaku researchers in Kyoto described it in the 1990s as NS-105, a cognition enhancer that modulates adenylate cyclase through metabotropic glutamate receptors in rat brain tissue (Oka et al., 1997).

After clinical trials for vascular dementia, it was tested as NFC-1 in adolescents with ADHD and glutamate-receptor gene variants (Elia et al., 2018).

The Nippon Shinyaku studies and the 2018 trial used fasoracetam monohydrate, which PubChem lists as CID 10198262 (C₁₀H₁₈N₂O₃, 214.26 g/mol, CAS 2055646-53-0).

Published work on fasoracetam falls into six areas. Receptor and behavior data come from one company's 1997 to 2000 rodent studies; human data come from small or unpublished trials.

Metabotropic glutamate receptors and cAMP

In rat cerebral cortex membranes, NS-105 at 10 nM to 1 µM inhibited forskolin-stimulated cAMP formation, yet raised it after pertussis toxin pretreatment. The mGluR agonist 1S,3R-ACPD mimicked both actions, an mGluR antagonist blocked them, and NS-105 did not affect binding at a range of neurotransmitter receptors (Oka et al., 1997).

Cultured mouse cortical neurons showed the same two-way pattern, and NS-105 damped agonist-driven phosphoinositide turnover (Oka et al., 1997). Subtype antagonists and antisense oligonucleotides traced the inhibition to group II (mGlu2, mGlu3) and group III (mGlu4, mGlu7) receptors and the rise to group I (Hirouchi et al., 2000). Models: rat cortical membranes and mouse cortical neurons.

GABA-B and cholinergic findings

In rat cortical slices, the GABA-B agonist baclofen no longer inhibited cAMP accumulation when NS-105 was present (Oka et al., 1997). Repeated NS-105 raised GABA-B receptor numbers in rat cerebral cortex without changing beta-adrenoceptor or 5-HT2 binding, and it did not inhibit monoamine uptake or alter brain monoamine levels (Shimidzu et al., 1997). At 10 mg/kg it raised cortical acetylcholine release, and it enhanced high-affinity choline uptake in lesioned or pentobarbital-exposed rats without changing choline acetyltransferase activity (Ogasawara et al., 1999). Models: rat brain slices and rats.

Learning and behavior models in rats

NS-105 was tested against memory disruption from scopolamine, nucleus basalis lesions, the cholinotoxin AF64A, baclofen, cerebral ischemia and electroconvulsive shock in passive avoidance and radial arm maze tasks, and showed anti-amnesic actions in a variety of these models.

Among reference drugs, aniracetam reversed the scopolamine deficit while bifemelane, idebenone and indeloxazine did not, and only NS-105 reversed the baclofen deficit (Ogasawara et al., 1999). At 1 to 100 mg/kg by mouth it shortened immobility in the forced swimming test, and repeated exposure reversed escape failure after inescapable footshock, a learned helplessness model (Shimidzu et al., 1997). Model: rats.

Pharmacokinetics and solid forms

With carbon-14-labeled NS-105 in rats, dogs and monkeys, intravenous half-lives were 0.67, 2.1 and 1.3 hours, and oral systemic availability was 97, 90 and 79 percent. Most was excreted unchanged in urine, and serum protein binding was under 3.3 percent in every species tested, including human serum (Mukai et al., 1999). X-ray crystallography found two hydrated forms and one non-hydrated form; hydrate form I was the most stable under ambient conditions and melted at 57°C, which the authors said could complicate formulation and storage (Harmsen et al., 2017). Models: rats, dogs and monkeys; crystals.

Development for vascular dementia

Nippon Shinyaku developed NS-105 for cerebrovascular disease. In a Japanese study in 7 elderly and 7 young healthy men, a single tablet gave higher peak plasma levels and exposure in the elderly, mainly from lower renal clearance (Kumagai et al., 1999). The 2018 ADHD paper states that the compound had been through phase I to III trials for vascular dementia, but PubMed indexes no efficacy data from that program, and the same authors called it a compound not previously registered (Elia et al., 2018). Model: human clinical studies.

ADHD and later trials

The 2018 phase 1 study enrolled 30 adolescents aged 12 to 17 with ADHD and copy number variants in mGluR network genes. Pharmacokinetic profiling was followed by a single-blind placebo week and 4 weeks of symptom-guided step-ups. Against the placebo week, mean CGI-I scores fell from 3.79 to 2.33 and CGI-S scores from 4.83 to 3.86 (both P < 0.001), parent Vanderbilt scores changed significantly in Tier 1 variant carriers, and adverse event frequency did not differ between placebo and active weeks; the authors attributed none of three serious adverse events to the compound.

The study was single-site and otherwise open-label, and the senior author disclosed founding neuroFix, later owned by Aevi Genomic Medicine (Elia et al., 2018). A 2019 systematic review listed fasoracetam (NFC-1, AEVI-001) among compounds in randomized ADHD trials (Nageye and Cortese, 2019).

Three double-blind, placebo-controlled Aevi trials (NCT02777931, NCT03265119, NCT03609619) posted outcome data on ClinicalTrials.gov but not in PubMed: mean ADHD Rating Scale changes were close to placebo, with no statistical comparison posted. A crossover phase 2 trial of fasoracetam monohydrate, coded NB-001, in 22q11.2 deletion syndrome (NCT05290493) posted no statistically significant global impression difference from placebo. Model: human clinical studies.