Synthesis and Evaluation of Fluorinated Aporphines: Potential Positron Emission Tomography Ligands for D<sub>2</sub> Receptors

Sromek, Anna W.; Si, Yu-Gui; Zhang, Tangzhi; George, Susan R.; Seeman, Philip; Neumeyer, John L.

doi:10.1021/ml1001689

Cited by 18 publications

(28 citation statements)

References 41 publications

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“…First, MCL-536 has very high D 2 high /D 3 selectivity (185) and binding affinity to D 2 high ( K i = 0.54 nM). 24 Second, the phenol derivatives are more stable than the catechols, which decompose quickly on synthesis and workup. Furthermore, we envisioned that the radiofluorination of the appropriate tosyl precursor of 1 might be accomplished in a single step, thus avoiding the need to use a protecting group on the phenol.…”

Section: Resultsmentioning

confidence: 99%

“…Morphine hydrochloride was supplied by Mallinckrodt (St. Louis, MO). MCL-536 ( 1 ) was prepared as described in the literature 24 and used as reference materials for the indirect characterization of the 18 F-labeled compounds.…”

Section: Methodsmentioning

confidence: 99%

“…22,23 We recently reported the synthesis and in vitro binding affinities for the D 1 , D 2 , and D 3 high- and low affinity states of the twelve fluorinated ( 19 F) aporphines and found that substituents in position 2 of the aporphine modulated the dopaminergic receptor potency and D 2 /D 3 selectivity of such compounds. 24 One of these analogs, MCL-536 (Figure 1), was found to possess high in vitro D 2 high affinity ( K i = 0.54 nM), excellent selectivity against other DA receptors, and ideal ClogP value (ideally less than 5). Further development as a 18 F radioligand is reported here.…”

Section: Introductionmentioning

confidence: 99%

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

Sromek

Zhang

Akurathi

et al. 2014

Labelled Comp Radiopharmac

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Sromek

Zhang

Akurathi

et al. 2014

Labelled Comp Radiopharmac

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“…The standard MCL-524 was prepared according to previously reported methods (15). The synthesis of the corresponding tosylated precursor MCL-556 is described in the supplemental information (supplemental materials are available at http://jnm.snmjournals.org).…”

Section: Methodsmentioning

confidence: 99%

“…1). This compound has nanomolar affinity in vitro to the D 2 receptor in a state of high affinity (D 2 high ) (3.7 nM) (15), and the radionuclide can be remotely introduced into the substituent at the 2-position. After radiosynthesis, 18 F-MCL-524 was evaluated by PET in cynomolgus monkeys.…”

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confidence: 99%

¹⁸F-MCL-524, an ¹⁸F-Labeled Dopamine D₂ and D₃ Receptor Agonist Sensitive to Dopamine: A Preliminary PET Study

et al. 2014

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PET has been used to examine changes in neurotransmitter concentrations in the living brain. Pioneering PET studies on the dopamine system have used D2 and D3 receptor (D2/D3) antagonists such as 11C-raclopride. However, more recently developed agonist radioligands have shown enhanced sensitivity to endogenous dopamine. A limitation of available agonist radioligands is that they incorporate the short-lived radioisotope 11C. In the current study, we developed the 18F-labeled D2/D3 receptor agonist (R)-(−)-2-18F-fluoroethoxy-N-n-propylnorapomorphine (18F-MCL-524). Methods In total, 10 PET measurements were conducted on 5 cynomolgus monkeys. Initially, the binding of 18F-MCL-524 was compared with that of 11C-MNPA in 3 monkeys. Second, the specificity of 18F-MCL-524 binding was examined in pretreatment studies using raclopride (1.0 mg/kg) and D-amphetamine (1.0 mg/kg). Third, a preliminary kinetic analysis was performed using the radiometabolite-corrected arterial input function of the baseline studies. Finally, 2 whole-body PET measurements were conducted to evaluate bio-distribution and radiation dosimetry after intravenous injection of 18F-MCL-524. Results 18F-MCL-524 entered the brain and provided striatum-to-cerebellum ratios suitable for reliable quantification of receptor binding using the multilinear reference tissue model. Mean striatal nondisplaceable binding potential (BPND) values were 2.0 after injection of 18F-MCL-524 and 1.4 after 11C-MNPA. The ratio of the BPND values of 18F-MCL-524 and 11C-MNPA was 1.5 across striatal subregions. After administration of raclopride and D-amphetamine, the 18F-MCL-524 BPND values were reduced by 89% and 56%, respectively. Preliminary kinetic analysis demonstrated that BPND values obtained with the 1-tissue- and 2-tissue-compart-ment models were similar to values obtained with the multilinear reference tissue model. Estimated radiation doses were highest for gallbladder (0.27 mSv/MBq), upper large intestine (0.19 mSv/MBq), and small intestine (0.17 mSv/MBq). The estimated effective dose was 0.035 mSv/MBq. Conclusion The 18F-labeled agonist 18F-MCL-524 appears suitable for quantification of D2/D3 receptor binding in vivo, and the results encourage extension to human studies. The longer half-life of 18F makes 18F-MCL-524 attractive for studies on modulation of the dopamine concentration—for example, in combination with simultaneous measurement of changes in blood-oxygen-level–dependent signal using bimodal PET/functional MRI.

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Hunting for the high‐affinity state of G‐protein‐coupled receptors with agonist tracers: Theoretical and practical considerations for positron emission tomography imaging

Shalgunov

Waarde

Booij

et al. 2018

Medicinal Research Reviews

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The concept of the high‐affinity state postulates that a certain subset of G‐protein‐coupled receptors is primarily responsible for receptor signaling in the living brain. Assessing the abundance of this subset is thus potentially highly relevant for studies concerning the responses of neurotransmission to pharmacological or physiological stimuli and the dysregulation of neurotransmission in neurological or psychiatric disorders. The high‐affinity state is preferentially recognized by agonists in vitro. For this reason, agonist tracers have been developed as tools for the noninvasive imaging of the high‐affinity state with positron emission tomography (PET). This review provides an overview of agonist tracers that have been developed for PET imaging of the brain, and the experimental paradigms that have been developed for the estimation of the relative abundance of receptors configured in the high‐affinity state. Agonist tracers appear to be more sensitive to endogenous neurotransmitter challenge than antagonists, as was originally expected. However, other expectations regarding agonist tracers have not been fulfilled. Potential reasons for difficulties in detecting the high‐affinity state in vivo are discussed.

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Synthesis and Evaluation of Fluorinated Aporphines: Potential Positron Emission Tomography Ligands for D₂ Receptors

Cited by 18 publications

References 41 publications

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

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

¹⁸F-MCL-524, an ¹⁸F-Labeled Dopamine D₂ and D₃ Receptor Agonist Sensitive to Dopamine: A Preliminary PET Study

Hunting for the high‐affinity state of G‐protein‐coupled receptors with agonist tracers: Theoretical and practical considerations for positron emission tomography imaging

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Synthesis and Evaluation of Fluorinated Aporphines: Potential Positron Emission Tomography Ligands for D2 Receptors

Cited by 18 publications

References 41 publications

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

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

18F-MCL-524, an 18F-Labeled Dopamine D2 and D3 Receptor Agonist Sensitive to Dopamine: A Preliminary PET Study

Hunting for the high‐affinity state of G‐protein‐coupled receptors with agonist tracers: Theoretical and practical considerations for positron emission tomography imaging

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Synthesis and Evaluation of Fluorinated Aporphines: Potential Positron Emission Tomography Ligands for D₂ Receptors

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

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

¹⁸F-MCL-524, an ¹⁸F-Labeled Dopamine D₂ and D₃ Receptor Agonist Sensitive to Dopamine: A Preliminary PET Study