Tanjore K. Narayanan

11C-l-Methionine Positron Emission Tomography in the Clinical Management of Cerebral Gliomas

Positron emission tomography (PET) using l-[methyl-11C]-methionine (MET) is the most popular amino acid imaging modality in oncology, although its use is restricted to PET centers with an in-house cyclotron facility. This review focuses on the role of MET–PET in imaging of cerebral gliomas. The biological background of tumor imaging with methionine is discussed with particular emphasis on cellular amino acid transport, amino acid utilization in brain, normal metabolism of methionine, and its alterations in cancer. The role of MET–PET in clinical management of cerebral gliomas in initial diagnosis, differentiation of tumor recurrence from radiation injury, grading, prognostication, tumor-extent delineation, biopsy planning, surgical resection and radiotherapy planning, and assessment of response to therapy is also reviewed in detail.

D2/D3 dopamine receptor binding with [F-18]fallypride in thalamus and cortex of patients with schizophrenia

BACKGROUND Abnormalities in the dopaminergic system are implicated in schizophrenia. [F-18]fallypride is a highly selective, high affinity PET ligand well suited for measuring D2/D3 receptor availability in the extrastriatal regions of the brain including thalamus, prefrontal, cingulate, and temporal cortex, brain regions implicated in schizophrenia with other imaging modalities. METHODS Resting [F-18]fallypride PET studies were acquired together with anatomical MRI for accurate coregistration and image analysis on 15 drug naïve schizophrenics (10 men, 5 women, mean age 28.5 years) and 15 matched controls (9 men, 6 women, mean age 27.4 years). Dopamine D2/D3 receptor levels were measured as binding potential (BP). The fallypride BP images of each subject were spatially normalized and subsequently smoothed for group comparison. Measures of significance between the schizophrenic and control groups were determined using statistical parametric mapping (SPM). The medial dorsal nucleus and pulvinar were also traced on coregistered MRI for detailed assessment of BP in these regions. RESULTS The thalamus of patients with schizophrenia had lower [F-18]fallypride BP than normal controls and this was the brain area with the greatest difference (range -8.5% to -27.2%). Left medial dorsal nucleus and left pulvinar showed the greatest decreases (-21.6% and -27.2% respectively). The patients with schizophrenia also demonstrated D2/D3 BP reduction in the amygdala region, cingulate gyrus, and the temporal cortices. CONCLUSIONS These findings suggest that drug naïve patients with schizophrenia have significant reductions in extrastratial D2/D3 receptor availability. The reductions were most prominent in regions of the thalamus, replicating other studies both with high affinity D2/D3 ligands and consistent with FDG-PET studies, further supporting the hypothesis of thalamic abnormalities in this patient population.

Evaluation of dopamine D-2 receptor occupancy by clozapine, risperidone, and haloperidol in vivo in the rodent and nonhuman primate brain using 18F-fallypride

We have used the high-affinity dopamine D-2 receptor radioligand, 18F-fallypride for evaluating receptor occupancy by the antipsychotic drugs, clozapine, risperidone, and haloperidol in rodents and nonhuman primates. In rodents, clozapine (0.1 mg/kg to 100 mg/kg) competed with 18F-fallypride at all the doses administered. At doses over 40 mg/kg, clozapine was able to displace all the administered 18F-fallypride. A pseudobiphasic profile of receptor occupancy by clozapine was observed. This behavior was compared with such other neuroleptics as risperidone and haloperidol that exhibited over 90% receptor occupancy at doses over 0.1 mg/kg and did not exhibit a biphasic nature. Dopamine D-2 receptor occupancy in the monkeys was studied using positron emission tomography (PET) after acute subcutaneous doses of the various drugs. At therapeutically relevant doses, clozapine, risperidone, and haloperidol were able to compete significantly with the binding of 18F-fallypride in all brain regions in rhesus monkeys, and our analyses indicate that these drugs (clozapine, risperidone, and haloperidol) do not discriminate between the striatal (caudate and putamen) and the extrastriatal (thalamus and cortical regions) dopamine receptors. The following extent of D-2 receptor occupancies were measured in the monkey brain using PET: clozapine ≈70% (dose of 9.7 mg/kg), risperidone ≈75% (0.05 mg/kg), and haloperidol ≈90% (0.05 mg/kg).

Quantitation of striatal and extrastriatal D‐2 dopamine receptors using PET imaging of [18F]fallypride in nonhuman primates

[18F]Fallypride is a highly selective, high‐affinity dopamine D‐2 receptor ligand. The high affinity, KD = 30 pM, makes it a suitable candidate for visualizing both striatal and extrastriatal binding in the brain. In this work, dynamic PET studies of two macaque monkeys were acquired along with arterial plasma samples. Compartmental analysis and Logan plots were used to analyze the striatum, thalamus, frontal, and temporal cortices and to validate a reference region of analysis which yields a distribution volume ratio (DVR). The cerebellum was used as the reference region. The results indicate that all methods of analysis are in close agreement over all the analyzed regions in the brain. The average DVRs for the two monkeys was found to be: caudate = 26, putamen = 29, thalamus = 3.8, frontal ctx = 1.7, and temporal ctx = 1.7 on a high‐resolution PET scanner. It was found that a scan time of 2 h is needed to accurately estimate the DVR for all regions of the brain. The striatal regions require the longest to linearize and are the most sensitive to variations in the average tissue‐to‐plasma efflux constant, k̄2. For the extrastriatal regions, the effect of the k̄2 term on DVR calculation is negligible. Repeatability measurements for all regions were found to be within 10% using the DVR parameter. Synapse 38:71–79, 2000.

11C-Methionine PET for Grading and Prognostication in Gliomas: A Comparison Study with 18F-FDG PET and Contrast Enhancement on MRI

The aim of this study was to compare the grading and prognostic value of l-[methyl-11C]-methionine (11C-MET) PET in glioma patients with 18F-FDG PET and contrast-enhanced MRI. Methods: Patients (n = 102) with histopathologically confirmed gliomas were followed up for an average of 34.6 ± 3.8 mo after PET. The median survival was 18 ± 4.7 mo in the high-grade glioma group and 58 ± 27 mo in the low-grade glioma group. Patients underwent 18F-FDG PET, 11C-MET PET, and MRI in the diagnostic and preoperative stage. The ratio of the mean standardized uptake value in the tumor to mean standardized uptake value in contralateral normal cortex (T/N ratio) was calculated. Kaplan–Meier survival analysis and ANOVA were performed. Results: T/N ratios for 11C-MET PET and 18F-FDG PET were significantly higher in high-grade gliomas than in low-grade gliomas (2.15 ± 0.77 vs. 1.56 ± 0.74, P < 0.001, and 0.85 ± 0.61 vs. 0.63 ± 0.37, P < 0.01, respectively). Median survival was 19 ± 5.4 mo in patients with a T/N ratio greater than 1.51 for 11C-MET PET and 58 ± 26.7 mo in those with a T/N ratio less than 1.51 (P = 0.03). Among the LGGs, median survival was lower in patients with a mean T/N ratio greater than 1.51 for 11C-MET PET (16 ± 10 mo; 95% confidence interval, 1–36 mo) than in those with a T/N ratio less than 1.51 (P = 0.04). No significant difference in survival in LGGs was based on 18F-FDG uptake and MRI contrast enhancement. Conclusion: 11C-MET PET can predict prognosis in gliomas and is better than 18F-FDG PET and MRI in predicting survival in LGGs.

Measuring the in Vivo Binding Parameters of [18F]-Fallypride in Monkeys Using a PET Multiple-Injection Protocol

The goal of this work was to quantify the in vivo transport and binding parameters of [F-18]fallypride and the D2/D3 receptor density (B′max) in both the striatal (putamen, caudate, ventral striatum) and extrastriatal regions (thalamus, amygdala, cerebellum, temporal and frontal cortices) of the rhesus monkey brain. Multiple-injection PET experimental protocols with injections of radiolabeled and unlabeled doses of fallypride were used to estimate the K1, k2, kon/VR, koff and B′max kinetic parameters. The experimental design was chosen using the D-optimal criterion to maximize the precision of the estimated binding parameters for the various brain regions. There was a significant range in B′max for the putamen (27pmol/mL), caudate (23pmol/mL), ventral striatum (14pmol/mL), thalamus (1.8pmol/mL) and amygdala (0.9pmol/mL). Significant receptor binding was also found in the cortical regions. Knowledge of these in vivo rate constants serves as a necessary step in using [F-18]fallypride PET to measure D2/D3 receptor density and drug occupancy in clinical research applications. We believe the precise parameter estimates derived from these complicated experimental protocols are necessary for proper application of drug occupancy and clinical research studies with [F-18]fallypride, which often rely on the validity of assumptions regarding the model parameters.

Measuring dopamine neuromodulation in the thalamus: Using [F-18]fallypride PET to study dopamine release during a spatial attention task

We used the highly selective D2/D3 dopamine PET radioligand [F-18]fallypride to demonstrate that cognitive task induced dopamine release can be measured in the extrastriatal region of the thalamus, a region containing 10-fold fewer D2 dopamine receptors than the striatum. Human studies were acquired on 8 healthy volunteers using a single [F-18]fallypride injection PET imaging session. A spatial attention task, previously demonstrated to increase FDG uptake in the thalamus, was initiated following a period of radioligand uptake. Thalamic dopamine release was statistically tested by measuring time-dependent alterations in the kinetics (focusing on specific binding) of the [F-18]fallypride using the linearized extension of the simplified reference region model. Voxel-based analysis of the dynamic PET data sets revealed a high correlation (r = 0.86, P = 0.0067) between spatial attention task performance and thalamic dopamine release. Various aspects of the kinetic model were analyzed to address concerns such as blood flow artifacts and model bias, as well as issues with task timing and regional variations in D2/D3 receptor density. In addition to the thalamus, measurement of dopamine neuromodulation using [F-18]fallypride and a single injection PET protocol can be extended to other extrastriatal regions of the brain, such as the amygdala, hippocampus, and regions of the temporal cortex. However, issues of task timing and detection sensitivity will vary depending on regional D2/D3 dopamine receptor density. Measurements of extrastriatal dopamine neuromodulation hold great promise to further our understanding of extrastriatal dopamine involvement in normal cognition and neuropsychiatric pathology.

Measurement of d-amphetamine-induced effects on the binding of dopamine D-2/D-3 receptor radioligand, 18F-fallypride in extrastriatal brain regions in non-human primates using PET.

The ability to measure amphetamine-induced dopamine release in extrastriatal brain regions in the non-human primates was evaluated by using the dopamine D-2/D-3 receptor radioligand, (18)F-fallypride. These regions included the thalamus, amygdala, pituitary, temporal cortex and frontal cortex as well as putamen, caudate and ventral striatum. The positron emission tomography (PET) studies involved control studies, which extended to 3 h, and the amphetamine-challenge studies, which involved administration of d-amphetamine (approx. 0.5-1 mg/kg, i.v.). PET data analysis employed the distribution volume ratio method (DVR) in which the cerebellum was used as a reference region. Our results show a substantial decrease in the binding potential of (18)F-fallypride in extrastriatal regions: thalamus (-20%), amygdala (-39%) and pituitary (-14%). Putamen, caudate and ventral striatum also exhibited significant decreases (-20%). The decrease in (18)F-fallypride binding in the extrastriatal regions points to the importance of dopaminergic neurotransmission in these brain regions. Furthermore, our findings support the use of (18)F-fallypride to measure extrastriatal dopamine release.

A comparative study on the uptake and incorporation of radiolabeled methionine, choline and fluorodeoxyglucose in human astrocytoma.

PURPOSE The goal of this investigation was to evaluate uptake and incorporation of 2-deoxy-2-[18F]fluoro-D-glucose (FDG), 11C-methionine, and 11C-choline in 17 patients suspected of grade-II and grade-III tumors using positron emission tomography (PET) and use in vitro astrocytoma cell lines in order to support in vivo findings. METHODS Seventeen patients with suspected astrocytomas (9 grade-II and 8 grade-III) were studied by PET with FDG and 11C-methionine; and one patient (grade-III) with FDG, 11C-methionine and 11C-choline. Uptake of PET molecular imaging probe was quantitative based on tumor to corresponding contralateral-region uptake ratio, tumor to mean-cortical-uptake ratio, and tumor to white matter uptake ratio. This was correlated with World Health Organization histology grading system and clinical follow-up. Uptake and incorporation of 3H-methionine, 3H-choline and FDG into lipid, RNA, DNA, and protein were investigated in a grade-III human tumor brain-14 astrocytoma cell line. RESULTS A time-dependent increase in the total uptake of 3H-methionine, 3H-choline and FDG was observed in human tumor brain-14 astrocytoma-III cell line. 3H-methionine was incorporated predominantly into proteins (in excess of 40% at 1 h) while 3H-choline incorporated primarily into lipids (in excess of 60% at 1 hr). Total uptake of FDG was accounted for in the free-pool supernatant fraction. In all patients, PET images of 11C-methionine and FDG provided higher tumor to white matter ratios than tumor to corresponding contra-lateral region ratios and tumor to mean cortical uptake ratios. In grade II patients, FDG did not exhibit significant increase in tumor uptake, while 11C-methionine was a good predictor with ratios of approximately 1.50 +/- 0.48. In grade III patients, both FDG and 11C-methionine exhibited higher ratios than for grade II, with 11C-methionine being the greatest (ratios of 2.50 +/- 0.85), possibly suggesting enhanced protein synthesis. With respect to tumor delineating potential, 11C-choline may be equal to or slightly better than 11C-methionine in the subject evaluated with all three probes. CONCLUSIONS Results suggest that a combination of FDG and 11C-methionine is useful in the prediction of histological grade of astrocytomas. In addition, 11C-methionine is better than FDG in delineating tumor boundary for low-grade gliomas. In vitro results suggest that 3H-methionine is significantly incorporated into proteins and provides the major driving force in the uptake of 11C-methionine observed in PET images.

In vitro and in vivo evaluation of the binding of the dopamine D2 receptor agonist11C-(R,S)-5-hydroxy-2-(di-n-propylamino)tetralin in rodents and nonhuman primate

The in vitro autoradiographic binding characteristics as well as in vivo imaging characteristics of a dopamine D2 receptor agonist, (R,S)‐2‐(N‐propyl‐N‐1′‐11C‐propyl)amino‐5‐hydroxytetralin (11C‐5‐OH‐DPAT), were studied. In 3H‐spiperone assays using rat striata, 5‐OH‐DPAT exhibited an affinity of IC50 = 2.5 nM. In vitro autoradiographs in rat brain slices with 11C‐5‐OH‐DPAT revealed selective binding to the dopaminergic regions in the striata which was displaceable by sulpiride. Varying concentrations of dopamine displaced this selective binding of 11C‐5‐OH‐DPAT to the striata in rat brain slices. This selective binding to the striata was also removed in the presence of the GTP analog, 5′‐guanylylimidodiphosphate, indicative of the binding of 11C‐5‐OH‐DPAT to the high‐affinity state of the D2 receptor. Ex vivo autoradiographic study in rats exhibited selective binding of 11C‐5‐OH‐DPAT to the striata. A PET study in a rhesus monkey showed selective localization of 11C‐5‐OH‐DPAT in the striata and the ratio between striata and cerebellum approached approximately 2 at 40 min postinjection. Synapse 37:64–70, 2000.