A series of compounds structurally related to aripiprazole (1), an atypical antipsychotic and antidepressant used clinically for the treatment of schizophrenia, bipolar disorder, and depression, have been prepared and evaluated for affinity at D2-like dopamine receptors. These compounds also share structural elements with the classical D2-like dopamine receptor antagonists, haloperidol, N-methylspiperone, domperidone and benperidol. Two new compounds, 7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate (6) and 7-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate (7) were found to (a) bind to the D2 receptor subtype with high affinity (Ki values <0.3 nM), (b) exhibit >50-fold D2 versus D3 receptor binding selectivity and (c) be partial agonists at both the D2 and D3 receptor subtype.

Abstract2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-quinoline (MP-10), a specific PDE10A inhibitor (IC 50 = 0.18 nM with 100-fold selectivity over other PDEs), was radiosynthesized by alkylation of the desmethyl precursor with [ 11 C]CH 3 I, ~45% yield, > 92% radiochemical purity, > 370 GBq/μmol specific activity at end of bombardment (EOB). Evaluation in Sprague-Dawley rats revealed that [ 11 C]MP-10 had highest brain accumulation in the PDE10A enriched striatum, the 30 min striatum: cerebellum ratio reached 6.55. MicroPET studies of [ 11 C]MP-10 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.

Accumulation of misfolded α-synuclein in Lewy bodies and Lewy neurites is the pathological hallmark of Parkinson’s Disease (PD). To identify ligands having high binding potency toward aggregated α-synuclein, we synthesized a series of phenothiazine derivatives and assessed their binding affinity to recombinant α-synuclein fibrils using a fluorescent thioflavin T competition assay. Among 16 new analogues, the in vitro data suggest that compound 11b has high affinity to α-synuclein fibrils (Ki = 32.10 ± 1.25 nM) and compounds 11d, 16a and 16b have moderate affinity to α-synuclein fibrils (Ki ≈ 50 to 100 nM). Further optimization of the structure of these analogues may yield compounds with high affinity and selectivity for aggregated α-synuclein.

To identify suitable lipophilic compounds having high potency and selectivity for vesicular acetylcholine transporter (VAChT), a heteroaromatic ring or a phenyl group was introduced into the carbonyl-containing scaffold for VAChT ligands. Twenty new compounds with ALog D values between 0.53-3.2 were synthesized, and their in vitro binding affinities were assayed. Six of them (19a, 19e, 19g, 19k and 24a-b) displayed high affinity for VAChT (Ki = 0.93 – 18 nM for racemates) and moderate to high selectivity for VAChT over σ1 and σ2 receptors (Ki = 44 – 4400-fold). These compounds have a methyl or a fluoro substitution that provides the position for incorporating PET radioisotopes C-11 or F-18. Compound (-)-[11C]24b (Ki = 0.78 for VAChT, 900-fold over σ receptors) was successfully synthesized and evaluated in vivo in rats and nonhuman primates. The data revealed that (-)-[11C]24b has highest binding in striatum and has favorable pharmacokinetics in the brain.

A series of fluorine containing N-(2-methoxyphenyl)piperazine and N-(2-fluoroethoxy)piperazine analogues were synthesized and their affinities for human dopamine D2, D3 and D4 receptors were determined. Radioligand binding studies identified five compounds, 18a, 20a, 20c, 20e and 21e, which bind with high affinity at D3 (Ki = 0.17 to 5 nM) and moderate to high selectivity for D3 vs. D2 receptors (ranging from ∼25 to 163-fold). These compounds were also evaluated for intrinsic activity at D2 and D3 receptors using a forskolin-dependent adenylyl cyclase assay. This panel of compounds exhibits varying receptor subtype binding selectivity and intrinsic activity at D2 vs. D3 receptors. These compounds may be useful for behavioral pharmacology studies on the role of D2-like dopamine receptors in neuropsychiatric and neurological disorders. Furthermore, compound 20e, which has the highest binding affinity and selectivity for the D3 receptor (Ki = 0.17 nM for D3, 163-fold selectivity for D3 vs. D2 receptors) represents a candidate fluorine-18 radiotracer for in vivo PET imaging studies on the regulation of D3 receptor expression.