We present development and human application of a method for determining the regional cerebral density of the type 2 vesicular monoamine transporter (VMAT2) using positron emission tomography (PET) and [11C]dihydrotetrabenazine (DTBZ). Previous animal studies indicate striatal VMAT2 density is linearly related to the integrity of substantia nigra dopamine neurons and is not subject to drug- or lesion-compensatory regulation. In the present studies, kinetic compartmental modeling was employed to estimate blood-brain [11C]DTBZ transport (K1) and VMAT2 binding site density (tissue-to-plasma DTBZ distribution volume, DV) from the cerebral and plasma DTBZ time courses after intravenous tracer injection. In controls, we found reductions of putamen DTBZ DVwith advancing age, corresponding to losses of 0.77% per year in specific VMAT2 binding. Parkinson's disease (PD) patients had reduction in specific DTBZ DV in the putamen (-61%) and in the caudate nucleus (-43%). There was no overlap of lowest specific putamen DTBZ DV between individual elderly controls and PD patients. The present results indicate the suitability of [11C]DTBZ PET for objective quantification of nigrostriatal integrity, including evaluation of PD progression and its possible therapeutic modification.

(+)-alpha-[11C]Dihydrotetrabenazine (DTBZ) binds to the vesicular monoamine transporter (VMAT2) located in presynaptic vesicles. The purpose of this work was to evaluate various model configurations for analysis of [11C]DTBZ with the aim of providing the optimal measure of monoamine vesicular transporter density obtainable from a single dynamic PET study. PET studies on seven young normal volunteer subjects, ages 20-35, were performed following i.v. injection of 666 +/- 37 MBq (18 +/- 1 mCi) of (+)-alpha-[11C]DTBZ. Dynamic acquisition consisted of a 15-frame sequence over 1 h. Analysis methods included both creation of pixel-by-pixel functional images of transport (K1) and binding (DVtot) and nonlinear least-squares analysis of volume-of-interest data. Pixel-by-pixel calculations were performed for both two-compartment weighted integral calculations and slope-intercept estimations from Logan plots. Nonlinear least-squares analysis was performed applying model configurations with both two-compartments, estimating K1 and DVtot and three compartments, estimating K1-k4. For the more complex configuration, we examined the stability of various binding-related parameters including k3 (konBmax'), k3/k4 (Bmax'/Kd), DVsp[(K1/k2)(k3/k4)], and DVtot [K1/k2(1 + k3/k4)]. The three-compartment model provided significantly improved goodness-of-fit compared to the two-compartment model, yet did not increase the uncertainty in the estimate of the DVtot. Without constraining parameters in the three-compartment model fits, DVtot was found to provide a more stable estimate of binding density than either k3, k3/k4, or DVsp. The two-compartment least-squares analysis yielded approximately 10% underestimations of the total distribution. However, this bias was found to be very consistent from region to region as well as across subjects as indicated by the correlation between two- and three-compartment DVtot estimates of 0.997. We conclude that (+)-alpha-[11C]DTBZ and PET can provide excellent measures of VMAT2 density in the human brain.

No abstract

We used ["Cldihydrotetrabenazine, a new ligand for the type 2 vesicular monoamine transporter (vMAT2), with posi-tron emission tomography to study striatal monoaminergic presynaptic terminals in 4 patients with multiple system atrophy, 8 with sporadic olivopontocerebellar atrophy, and 9 normal control subjects. Specific binding in the striatum was significantly reduced in the multiple system atrophy patients as compared with the normal control group, with average reductions of 61% in the caudate nucleus (p = 0.002) and 58% in the putamen (p = 0.009). Smaller reductions were found in the sporadic olivopontocerebellar atrophy group, averaging 26% in the caudate nucleus (p = 0.05) and 24% in the putamen (p = 0.1 1). Mean blood-to-brain ["Cldihydrotetrabenazine transport (K,) was significantly different between groups only in the cerebellum, with values for the sporadic olivopontocerebellar atrophy group diminished compared with the normal control group. Cerebellar K, was not significantly decreased in the multiple system atrophy group. The finding of reduced striatal W T 2 in sporadic olivopontocerebellar atrophy patients suggests nigrostriatal pathology, indicating that some may later develop symptomatic extrapyramidal disease. Cilman, S, Frey KA, Koeppe RA, Juiick L, Little R, Vander Borght TM, Lohnian M, Martorello S, Lee LC, Jewett DM, Kilbourn MR. Decreased striatal monoaminergic terminals in olivopontocerebellar atrophy and multiple system atiophy demonstrated with positron emission tomography. Ann Neurol 1996;40:885-892 Multiple system atrophy (MSA) is a progressive neuro-logical disorder consisting of combinations of extra-pyramidal, pyramidal, cerebellar, and autonomic symptoms and signs [l-71. The term "possible MSA" is used for patients with only extrapyramidal symptoms that are poorly responsive or unresponsive to levodopa (striatonigral degeneration [SND]) and patients with a combination of cerebellar ataxia and extrapyramidal symptoms [2]. The term "probable MSA' pertains to patients with extrapyramidal symptoms poorly responsive or unresponsive to levodopa accompanied by auto-nomic symptoms with or without pyramidal and cere-bellar symptoms (Shy-Drager syndrome [SDS]) [2]. Similarly, the term "probable MSA' is applied to patients with cerebellar and autonomic symptoms with or without extrapyramidal and pyramidal symptoms [2]. The diagnosis of "definite MSA' requires a typical history and physical findings with subsequent postmor-tem verification [2]. In most patients with definite MSA, neuropathological examination demonstrates degenera-tivechanges in the cerebellum and brainstem as well as the basal ganglia and spinal cord [8]. The neuropathological changes in MSA include those seen with SND [9-121, SDS [3, 13-16], and olivopontocerebellar atrophy (OPCA) 13, 6-81. Neuronal loss and gliosis occur in the basal ganglia (putamen and globus pallidus), brainstem and cerebellum (substantial nigra, locus ceruleus, dorsal vagal nuclei, vestibular nuclei, inferior olives, pontine nu-clei, and cerebellar Purki...

Noninvasive measurement of liver regeneration with positron emission tomography has been attempted with 11C-thymidine; however, results were unsatisfactory using thymidine labeled on its methyl group. To evaluate whether the specificity of the method could be improved by modifying the labeling position of the tracer, thymidine labeled on its methyl group with 3H and thymidine labeled on its carbon 2 with 14C were injected in 22 hepatectomized rats either 1 hr (when DNA synthesis is not increased) or 24 hr after the surgical procedure (when the rate of DNA synthesis is maximal). Liver samples taken 10, 30 and 120 min after injection showed that, in contrast to 3H-radioactivity, 14C-radioactivity measured in whole tissue allowed a clear discrimination between regenerating and nonregenerating livers. In addition, 14C-radioactivity measured in whole tissue of regenerating livers correlated with the DNA radioactivity 10, 30 and 120 min after injection of the tracer. In contrast, no such correlation was found with the methyl-labeled thymidine. Analysis of the radioactive material present in the non-DNA fraction using ion exchange disks and high-performance liquid chromatography showed that 2-C-labeled thymidine was incorporated into DNA without accumulation of labeled metabolites whereas, for the methyl-labeled thymidine, almost all radioactivity was related to degradative products. Therefore the evaluation of the liver regeneration with the 2-C-labeled thymidine, which does not require cellular fractionation, should be suited for noninvasive measurement with positron emission tomography.