¹⁸F-MCL-524, an ¹⁸F-Labeled Dopamine D₂ and 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 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.

Synthesis and Evaluation in Rats of the Dopamine D2/3Receptor Agonist18F-AMC20 as a Potential Radioligand for PET

“…However, 18 F-AMC20 is inferior to existing 11 C-labeled D 2/3 agonists (13,21,22) in terms of baseline striatal BP ND (0.49-0.59 vs. .0.8) and, apparently, also in terms of sensitivity to raclopride treatment. The higher nonspecific binding of 18 F-AMC20, resulting from its considerably higher lipophilicity (LogD, 2.33 6 0.03) relative to 18 F-FEt-AMC13 (LogD, 1.67 6 0.07), seems to have prevented 18 F-AMC20 from attaining a high signal-to-noise ratio despite its high affinity toward D 2/3 RHigh.…”

“…The scope of use of 11 C tracers is limited by the short half-life of 11 C (20.4 min), whereas tracers labeled with longer-living radioisotopes such as 18 F (half-life, 109.8 min) have a much greater potential. (R)-(2)-2-18 F-fluoroethoxy-N-n-propylnorapomorphine ( 18 F-MCL-524), an 18 F-labeled apomorphine derivative, showed promising results in monkeys (13) but has not yet been reported to be used in humans.…”

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.…”

Methamphetamine-sensitized rats show augmented dopamine release to methylphenidate stimulation: A positron emission tomography using [18F]fallypride

“…Antagonists bind with equal affinity to the two affinity states of the receptor and do not provide information on the fraction of receptors in the high-affinity state. To overcome this limitation, agonist radioligands, binding readily with the high-affinity state D 2 receptor, have recently been developed, including 18 F-MCL-524 (Finnema et al, 2014), 11 C-NPA (Hwang et al, 2000), 11 C-MNPA (Finnema et al, 2005), and 11 C-4-propyl-9-hydroxynaphthoxazine (Wilson et al, 2005). The advantage of these agonist radioligands is that they are more displaceable than the antagonist radiotracer [ 11 C]raclopride after an acute psychostimulant-challange.…”