Convenient synthesis of ¹⁸F‐radiolabeled R‐(−)‐N‐n‐propyl‐2‐(3‐fluoropropanoxy‐11‐hydroxynoraporphine

Abstract

Aporphines are attractive candidates for imaging D2 receptor function because, as agonists rather than antagonists, they are selective for the receptor in the high affinity state. In contrast, D2 antagonists do not distinguish between the high and low affinity states, and in vitro data suggests that this distinction may be important in studying diseases characterized by D2 dysregulation, such as schizophrenia and Parkinson’s disease. Accordingly, MCL-536 (R-(−)-N-n-propyl-2-(3-[18F]fluoropropanoxy-11-hydroxynoraporphine) was selected for labeling with 18F based on in vitro data obtained for the non-radioactive (19F) compound. Fluorine-18-labeled MCL-536 was synthesized in 70% radiochemical yield, >99% radiochemical purity and specific activity of 167 GBq/μmol (4.5 Ci/μmol) using p-toluenesulfonyl (tosyl) both as a novel protecting group for the phenol and a leaving group for the radiofluorination.

PET radiotracer development for imaging high‐affinity state of dopamine D2 and D3 receptors: Binding studies of fluorine‐18 labeled aminotetralins in rodents

“…Apomorphine analogs, 11 C-NPA in PET studies of nonhuman primates clearly showed binding to the caudate-putamen, similar to that found for 11 C-raclopride (Finnema et al, 2009; Hwang et al, 2005). More recently, agonists 18 F-MCL-524, apomorphine analogs (Finnema et al, 2014; Sromek et al, 2014) and 18 F-aminomethylchroman analogs (Shalgunov et al, 2015a,b) have been reported for imaging dopamine D2 and D3 receptors. 11 C-PHNO is a modified aminotetralin derivative and has high-affinity for D2 and D3 receptor subtypes thus suggesting that PHNO binds to D2-high affinity state (HA) and D3 receptors.…”

“…Therefore, selective D2 and D3 receptor imaging agents will be more useful in evaluating efficacy of treatment regimens. Development of selective agents have been actively pursued; successful aminotetralin‐based, piperazine‐based, apomorphine‐based compounds have been reported (e.g., Mach et al, ; Mukherjee et al, ; Shi et al, ; Sromek et al, ).…”

New Dopamine D2 Receptor Agonist, [3H]MCL-536, for Detecting Dopamine D2high Receptors in Vivo

“…We have developed an aporphine agonist, R-(−)-2-(3fluoropropanoxy-11-hydroxy-N-n-propyl(1,2-[ 3 H])noraporphine [ 3 H]MCL-536, which binds with high affinity to dopamine D2 receptors but not to other receptors of the D2 family. 31 Additionally, MCL-536 exhibited no affinity or low affinity for other receptors tested, including serotonin, αand βadrenergic, benzodiazepine, GABAA, muscarinic, sigma, kappa, and mu opioid receptors, as well as dopamine, serotonin, and norepinephrine transporters and translocator proteins (NIMH, Psychoactive Drug Screening Program, North Carolina). Herein, we describe the further characterization of this novel agonist ligand with regard to its binding affinities to human D2 receptors expressed in Chinese hamster ovary (CHO) cells.…”

The High Affinity Dopamine D2 Receptor Agonist MCL-536: A New Tool for Studying Dopaminergic Contribution to Neurological Disorders

“…23 MCL-536 is an aporphine agonist that binds with high affinity to dopamine D 2 receptors but not to other receptors of the D 2 receptor family. 24,25 MCL-536 also exhibits little to no affinity for other receptors found in the brain. 25 MCL-536 has a high affinity for the D 2 receptor in its active state, with a K d value of 0.8 nM and K i values of 0.16 nM for (R)-(−)-N-npropylnorapomorphine (NPA) and 0.9 nM for raclopride, respectively, in competition binding assays.…”

“…We have synthesized a highly promising high affinity dopamine D 2 receptor ligand, R -(−)-2-(3-fluoropropanoxy-11-hydroxy-N- n -propyl­(1,2-[ 3 H])­noraporphine ([ 3 H]­MCL-536), as a potential tritiated radioligand for applications in receptor binding assays and autoradiography studies in vitro . MCL-536 is an aporphine agonist that binds with high affinity to dopamine D 2 receptors but not to other receptors of the D 2 receptor family. , MCL-536 also exhibits little to no affinity for other receptors found in the brain . MCL-536 has a high affinity for the D 2 receptor in its active state, with a K d value of 0.8 nM and K i values of 0.16 nM for ( R )-(−)- N - n -propylnorapomorphine (NPA) and 0.9 nM for raclopride, respectively, in competition binding assays …”