Dopamine receptors (DARs) are members of the G protein-coupled receptors (GPCRs) superfamily which play a critical role in cell signaling processes, especially modulating the transfer of information within the nervous system [1]. Amongst DARs, the D2 receptor is arguably one of the most validated drug targets in neurology and psychiatry [2]. There is a strong correlation between the clinical doses of neuroleptics and their affinity for brain D2 receptors [3]. Despite numerous attempts of producing D2 selective modulators, current drugs display poor selectivity between D2 and D3 DARs. This is because D2 is closest to D3 in terms of sequence homology and signaling transduction pathways hence it pose a challenge to selectively regulate the two receptors [4, 5]. However given the success, a potent and selective D2 DAR antagonist would be of particular interest for the treatment of a variety of related CNS diseases [6, 7]. Here we present the discovery of a novel series of selective small molecule D2 DAR antagonists from a quantitative high-throughput screen (qHTS) campaign. Optimized lead compound in this series exhibits an excellent D2versus D1, D3, D4 and D5 receptor selectivity. In a panel of GPCR binding assays, ML321 shows a cleaner profile compared to the best previously reported selective D2 DAR antagonist. Furthermore, ML321 showed good in vitro ADME data and in vivo pharmacokinetic (PK) properties. We therefore believe that this probe can be a very useful pharmacological tool to perform proof-of-concept studies in animal models and may be an ideal starting point for further development into drug-like molecules for the treatment of a variety of CNS diseases including Tourette’s syndrome, tardive dyskinesia, dystonia, Huntington’s chorea, and especially schizophrenia.