Assessment of receptor occupancy-over-time of two dopamine transporter inhibitors by [¹¹C]CIT and target controlled infusion

Figures & data

Figure 1. The response of [¹¹C]CIT in cerebellum was modeled from TACs from six previous experiments where the tracer was administered as an intravenous bolus. Error bars indicate standard deviation. The model curve was used to calculate the infusion scheme required to achieve pseudo steady state of tracer in cerebellum.

Figure 2. Target-controlled infusion to reach pseudosteady state of [¹¹C]CITin cerebellum. As expected, there was high uptake localized to striatum, as shown in a trans-axial projection of a representative subject (A). The pseudosteady state of [¹¹C]CITin cerebellum resulted in elevated, close to irreversible striatal uptake (B). Error bars indicate SEM (n = 5).

Table I. Kinetic parameters for [¹¹C]CIT PK/PD in striatum determined from the simplified reference tissue model. The majority of variation in BP and DVR is due to the elevated values in subject 3.

Parameter	Subject 1	Subject 2	Subject 3	Subject 4	Subject 5	Average	SEM
R1	0.58	1.09	1.47	1.17	0.84	1.03	0.15
k2	0.13	0.08	0.12	0.07	0.07	0.10	0.01
BP	3.85	4.18	8.14	4.69	5.87	5.34	0.78
DVR	4.85	5.18	9.14	5.69	6.87	6.34	0.78
DVR ref	1	1	1	1	1	1	-

Figure 3. Intravenous administration at 60 minutes of either bupropion 5 mg/kg (A) or GBR-12909 5 mg/kg(B). Infusion is aimed at pseudo steady state of [¹¹C]CIT in cerebellum. Best fit occupancy models for each DAT inhibitor are presented as black lines.

Table II. Occupancy model parameters describing the initial pharmacodynamics of bupropion and GBR-12909. Best fit was obtained by minimizing the residual sum of squares (RSS).

Parameter	Unit	Bupropion	GBR-12909
Occ0	%	84.5	76.1
koff	min^-1	0.021	0.0
Model fit (RSS)		0.33	1.68