1. ^*Department of Biomathematics, UCLA School of Medicine, Los Angeles, California, U.S.A.
2. ^†Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, California, U.S.A.
3. ^‡Department of Radiological Sciences, UCLA School of Medicine, Los Angeles, California, U.S.A.

Correspondence: Sung-Cheng Huang, Department of Molecular and Medical Pharmacology, UCLA School of Medicine, 10833 Le Conte Avenue, B2-086A Center for the Health Sciences, Los Angeles, CA 90095, U.S.A., or Kooresh Shoghi-Jadid, Department of Biomathematics, UCLA School of Medicine, 10833 Le Conte Avenue, AV-617 Center for the Health Sciences, Los Angeles, CA 90095, U.S.A.

Received 8 December 1999; Revised 27 March 2000; Accepted 28 March 2000.

Abstract

The peripherally born metabolite of FDOPA, 3-O-Methyl-FDOPA (3OMFD), crosses the blood-brain barrier, thus complicating positron emission tomography-FDOPA (PET-FDOPA) data analysis. In previous reports the distribution volume (DV) of 3OMFD was constrained to unity. We have recently shown that the forward transport rate-constant of FDOPA (K_S1) and the cerebellum-to-plasma ratio (C_b/C_p), a measure for the DV of 3OMFD, are functions of plasma large neutral amino acid (LNAA) concentration. Given large interstudy and intersubject differences in plasma LNAA levels, variations in the DV of 3OMFD are significant. In this report, the authors propose a constraint on the DV of 3OMFD that accounts for these variations. Dynamic PET-FDOPA scans were performed on 12 squirrel monkeys and 12 vervet monkeys. Two sets of constraints were employed on the compartmental model-M1 or M2. In M1, the striatal DV of 3OMFD was constrained to unity; in M2, the striatal DV of 3OMFD was constrained to an estimate derived from the cerebellum. Striatal and cerebellar time-activity curves were fitted using FDOPA and 3OMFD plasma input functions. The estimate of K_S1 and that of the compartmental FDOPA uptake-constant (K_i), both obtained using M2, were adjusted to values corresponding to average LNAA levels. Finally, K_i was compared with the graphical uptake-constant (PK_i). With the use of constraint M2, intersubject variability of squirrel monkey k_S3 and K_i was reduced by 45% and 53%, respectively; and for vervet monkeys, by 54% and 44%, respectively. Intersubject variability of K₁ and K_i was further reduced after correction for variations in intersubject plasma LNAA levels (for squirrel monkeys, by 67% and 41%; for vervet monkeys, by 40% and 36%, respectively). K_i correlation to PK_i was enhanced to identity. Finally, average cerebellar k_C2 estimates were more than 2.5-fold higher than striatal k_S2 estimates (P < 0.0001). In modeling of PET-FDOPA data, it cannot be assumed that the DV of 3OMFD is unity. The cerebellar-derived constraint furnishes a reliable estimate for the DV of 3OMFD. Invoking the constraint and correcting for variations in plasma LNAA significantly reduced interstudy and intersubject variations in parameter estimates.