Positron Emission Tomography Quantification of [¹¹C]-(+)-PHNO Binding in the Human Brain

Abstract

The kinetic modeling of [ 11 C]-( + )-PHNO binding to the dopamine D 2/3 receptors in six human volunteers using positron emission tomography (PET) is described. [ 11 C]-( + )-PHNO is the first agonist radioligand for the D 2/3 in humans and as expected showed high uptake in caudate, putamen, globus pallidus (GP) and ventral striatum, and low uptake in cerebellum. A two-tissue compartment model (2CM) with four parameters was necessary to adequately fit time-activity data in all regions. Although a 2CM provided an excellent estimation of total distribution volumes, which were highly correlated with those obtained with the invasive Logan approach, it provided a poor identification of the k 3 /k 4 ratios. Coupling K 1 /k 2 between brain regions (Method C) or fixing K 1 /k 2 to the value obtained in cerebellum (Method D) enabled more stable estimates of k 3 /k 4 as compared with an unconstrained 2CM. The k 3 /k 4 obtained with Method D ranged from 0.1260.03 in cerebellum to 3.9360.77 in GP and were similar to those obtained when coupling K 1 /k 2 . Binding potentials (BPs) obtained using the simplified reference tissue model (BP SRTM ) ranged from 2.0860.34 in caudate to 3.5560.78 in GP and were highly correlated with k 3 /k 4 estimates obtained with Method D (r = 0.98). However, BP SRTM were 11%65% lower than values obtained with Method D. BPs derived using the noninvasive Logan approach were slightly lower but not significantly different than BP SRTM . This study demonstrates that [ 11 C]-( + )-PHNO can be used for the quantitative measurement of D 2/3 densities and should enable further studies of potential D 2/3 dysregulation in several important psychiatric and neurologic illnesses.

Serotonergic loss in motor circuitries correlates with severity of action-postural tremor in PD

“…Moreover, motor circuitry 5-HT dysfunctions correlate with severity of tremor on posture and action. It is possible that resting tremor possesses a serotonergic substrate related more specifically to postsynaptic mechanisms, as evidenced by Doder et al 18 Our study utilized 11 C-DASB, a marker of presynaptic SERT only; thus, we were unable to detect any influence of the postsynaptic mechanisms involved in resting tremor in our patients.…”

“…Postmortem 2 studies have shown loss of serotonergic (5-HT) projections in PD, although to a lesser extent than dopaminergic (DAergic) neurons. 11 C-DASB (11C-labeled 3-amino-4-[2-[(di(methyl)amino) methyl]phenyl]sulfanylbenzonitrile) PET imaging, a marker of serotonin transporter (SERT) binding, has shown that 5-HT dysfunction occurs early in PD 3 and that levels correlate with nonmotor symptoms such as depressive symptoms and alterations of body weight. 4,5 Whereas L-dopa and dopamine agonists successfully relieve bradykinesia and rigidity, the response of parkinsonian tremor is variable.…”

“…We hypothesized that PD tremor, unlike bradykinesia and rigidity, could be related to dysfunctions of the 5-HT system in areas related to motor function and we sought to investigate this in vivo using 11 C-DASB PET, a specific marker of the 5-HT transporter that can be used as an index of presynaptic 5-HT terminal integrity, 11,12 together with clinical observations. METHODS Clinical evaluation.…”

“…ANALYZE medical imaging software (version 8.1, Mayo Foundation) was used for processing the ROIs and TACs. 11 C-DASB nondisplaceable binding potential (BP ND ) (distribution volume ratio of a receptor-containing region to a reference region minus 1) 11,15 was estimated in each ROI using the Logan method. 16 The cerebellum, excluding the vermis, was used as a reference region for nonspecific binding.…”

Measurement Error Analysis for the Determination of Dopamine D2 Receptor Occupancy Using the Agonist Radioligand [11C]MNPA

“…K 1 /k 2 for both target and reference regions were same in this simulation study; however, in clinical situation, sometimes K 1 /k 2 values may vary from regions to regions (Ginovart et al, 2007) and these difference may introduce errors in BP ND when the ratio K 1 /k 2 is fixed.…”