18F-MCL-524, an 18F-labeled dopamine D2and D3 receptor agonist sensitive to dopamine: A preliminary PET study

Abstract

PET has been used to examine changes in neurotransmitter concentrations in the living brain. Pioneering PET studies on the dopamine system have used D 2 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 biodistribution 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 Damphetamine, 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-compartment 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 D 2/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. Copyright © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.