Measuring amphetamine-induced dopamine release in humans: A comparative meta-analysis of [¹¹C]-raclopride and [¹¹C]-(+)-PHNO studies

The radiotracers [¹¹C]-raclopride and [¹¹C]-(+)-PHNO are commonly used to measure differences in amphetamine-induced dopamine release between healthy persons and persons with neuropsychiatric diseases. As an agonist radiotracer, [¹¹C]-(+)-PHNO should theoretically be roughly 2.7 times more sensitive to displacement by endogenous dopamine than [¹¹C]raclopride. To date, only one study has been published comparing the sensitivity of these two radiotracers to amphetamine-induced dopamine release in healthy persons. Unfortunately, conflicting findings in the literature suggests that the dose of amphetamine they employed (0.3 mg/kg, p.o.) may not reliably reduce [¹¹C]-raclopride binding in the caudate. Thus, it is unclear whether the preponderance of evidence supports the theory that [¹¹C]-(+)-PHNO is more sensitive to displacement by amphetamine in humans than [¹¹C]-raclopride. In order to clarify these issues, we conducted a comparative meta-analysis summarizing the effects of amphetamine on [¹¹C]-raclopride and [¹¹C]-(+)-PHNO binding in healthy humans. Our analysis indicates that amphetamine given at 0.3 mg/kg, p.o. does not reliably reduce [¹¹C]-raclopride binding in the caudate. Second, the greater sensitivity of [¹¹C]-(+)-PHNO is evidenced at 0.5 mg/kg, p.o., but not at lower doses of amphetamine. Third, our analysis suggests that [¹¹C]-(+)-PHNO may be roughly 1.5 to 2.5 times more sensitive to displacement by amphetamine than [¹¹C]-raclopride in healthy persons. We recommend that future displacement studies with these radiotracers employ 0.5 mg/kg, p.o. of amphetamine with a dose, post-scan interval of at least 3 hr. Using this dose of amphetamine, [¹¹C]-raclopride studies should employ at least n = 34 participants per group, while [¹¹C]-(+)-PHNO studies should employ at least n = 6 participants per group, in order to be sufficiently powered (80%) to detect changes in radiotracer binding within the caudate.