Estimating Endogenous Dopamine Levels at D2 and D3 Receptors in Humans using the Agonist Radiotracer [11C]-(+)-PHNO

Abstract

Using positron emission tomography (PET) and an acute dopamine depletion challenge it is possible to estimate endogenous dopamine levels occupying dopamine D2/3 receptors (D2/3R) in humans in vivo. Our group has developed [(11)C]-(+)-PHNO, the first agonist radiotracer with preferential in vivo affinity for D3R. Thus, the use of [(11)C]-(+)-PHNO offers the novel possibility of (i) estimating in vivo endogenous dopamine levels at D2/3R using an agonist radiotracer, and (ii) estimating endogenous dopamine levels at D3R in extrastriatal regions such as the substantia nigra, hypothalamus, and ventral pallidum. Ten healthy participants underwent a [(11)C]-(+)-PHNO PET scan under baseline conditions and another under acute endogenous dopamine depletion achieved via oral administration of alpha-methyl-para-tyrosine (64 mg/kg). [(11)C]-(+)-PHNO binding was sensitive to acute dopamine depletion, allowing in vivo estimates of endogenous dopamine in D2R-rich regions (caudate and putamen), mixed D2/3R-rich regions (ventral striatum and globus pallidus), and extrastriatal D3R-rich regions (hypothalamus and ventral pallidum). Dopamine depletion decreased self-reported vigor, which was correlated with the reduction in dopamine levels in the globus pallidus. [(11)C]-(+)-PHNO is a suitable radiotracer for use in estimating endogenous dopamine levels at D2R and D3R in neuropsychiatric populations.

Lack of Age-Dependent Decrease in Dopamine D3 Receptor Availability: A [11C]-(+)-PHNO and [11C]-Raclopride Positron Emission Tomography Study

“…Data from these participants have been previously reported. [26][27][28] 11 C]-Raclopride. Therefore, the scanning order between the radiotracers was counter-balanced (11 female, age: 43 ± 17 years old).…”

Elevated Dopamine D2/3 Receptor Availability in Obese Individuals: A PET Imaging Study with [11C](+)PHNO

“…Another potential explanation for dissimilarities between this study and other studies that employed antagonist tracers may be due to endogenous dopamine competition. Without utilizing a pharmacologic intervention such as the tyrosine-hydroxylase inhibitor α-methly-para-tyrosine (AMPT) to deplete tonic dopamine (Abi-Dargham et al, 2000;Caravaggio et al, 2014;Laruelle et al, 1997;Martinez et al, 2009), our outcome measure, BP ND , reflects tracer bound to receptors not currently occupied by the endogenous neurotransmitter (ie, dopamine) and therefore measures receptor availability (Innis et al, 2007). [ 11 C](+)PHNO has been shown to be substantially more sensitive to endogenous dopamine competition (ie, increased tracer displacement resulting in lower BP ND ) compared with the antagonist tracers used in prior studies (Cropley et al, 2008;Gallezot et al, 2014a;Ginovart et al, 2006;Moerlein et al, 1997;Shotbolt et al, 2012;Willeit et al, 2008); thus, our receptor availability findings could also be due to OB individuals exhibiting lower levels of tonic dopamine.…”

The effect of striatal dopamine depletion on striatal and cortical glutamate: A mini-review

“…Acute dopamine depletion is possible in humans via administration of the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT). Challenges with AMPT have been successfully employed in conjunction with PET to estimate endogenous dopamine levels at D 2/3 R in living humans (Caravaggio et al, 2015;Caravaggio et al, 2014;Kegeles et al, 2010;Laruelle et al, 1997;Martinez et al, 2009;Verhoeff et al, 2001). Thus, measuring glutamate concentrations with 1 H-MRS before and after AMPT administration could help elucidate how dopamine depletion alters glutamatergic functioning in healthy persons and persons with neuropsychiatric diseases.…”

“…However, a negative correlation was observed between glutamate concentrations in the left prefrontal cortex and dopamine synthesis capacity in the left ventral striatum (r 2 = .17). Future PET studies examining dopamine synthesis capacity or endogenous dopaminergic tone (Caravaggio et al, 2014;Laruelle et al, 1997;Verhoeff et al, 2001) should also examine glutamate concentrations measured with 1 H-MRS in the dorsal striatum and cortex; in healthy persons and persons with neuropsychiatric diseases.…”