scholarly journals Imaging the GABA-Benzodiazepine Receptor Subtype Containing the α5-Subunit In Vivo with [11C]Ro15 4513 Positron Emission Tomography

2002 ◽  
Vol 22 (7) ◽  
pp. 878-889 ◽  
Author(s):  
Anne Lingford-Hughes ◽  
Susan P. Hume ◽  
Adrian Feeney ◽  
Ella Hirani ◽  
Safiye Osman ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Benzodiazepine Receptors ◽  
Benzodiazepine Receptor ◽  
Occipital Cortex ◽  
Input Function ◽  
Emission Tomography ◽  
Receptor Subtype ◽  
Receptor Localization ◽  
Positron Emission

There is evidence of marked variation in the brain distribution of specific subtypes of the GABA-benzodiazepine receptor and that particular subtypes mediate different functions. The α5-containing subtype is highly expressed in the hippocampus, and selective α5 inverse agonists (which decrease tonic GABA inhibition) are being developed as potential memory-enhancing agents. Evidence for such receptor localization and specialization in humans in vivo is lacking because the widely used probes for imaging the GABA-benzodiazepine receptors, [11C]flumazenil and [123I]iomazenil, appear to reflect binding to the α1 subtype, based on its distribution and affinity of flumazenil for this subtype. The authors characterized for positron emission tomography (PET) a radioligand from Ro15 4513, the binding of which has a marked limbic distribution in the rat and human brain in vivo. Competition studies in vivo in the rat revealed that radiolabeled Ro15 4513 uptake was reduced to nonspecific levels only by drugs that have affinity for the α5 subtype (flunitrazepam, RY80, Ro15 4513, L655,708), but not by the α1 selective agonist, zolpidem. Quantification of [11C]Ro15 4513 PET was performed in humans using a metabolite-corrected plasma input function. [11C]Ro15 4513 uptake was relatively greater in limbic areas compared with [11C]flumazenil, but lower in the occipital cortex and cerebellum. The authors conclude that [11C]Ro15 4513 PET labels in vivo the GABA-benzodiazepine receptor containing the α5 subtype in limbic structures and can be used to further explore the functional role of this subtype in humans.

scholarly journals Evaluation of Dopaminergic Presynaptic Integrity: 6-[18F]Fluoro-L-Dopa Versus 6-[18F]Fluoro-L-m-Tyrosine

1999 ◽  
Vol 19 (3) ◽  
pp. 278-287 ◽  
Author(s):  
D. J. Doudet ◽  
G. L.-Y. Chan ◽  
S. Jivan ◽  
O. T. DeJesus ◽  
E. G. McGeer ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Metabolic Pathway ◽  
Arterial Input Function ◽  
Occipital Cortex ◽  
Input Function ◽  
Emission Tomography ◽  
Dopa Decarboxylase ◽  
Positron Emission ◽  
Pet Scans

The effectiveness of 6-[18F]fluoro-L- m-tyrosine (6FMT) to evaluate dopamine presynaptic integrity was compared to that of 6-[18F]fluoro-L-dopa (6FDOPA) in vivo by positron emission tomography (PET). Six normal and six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -lesioned monkeys received 6FDOPA and 6FMT PET scans on separate occasions with identical scanning protocols. Four measures, the rate of uptake of tracer into striatum using either the arterial input function ( Ki) or the activity in the occipital cortex as the input function ( Kc), the rate of loss of striatal radioactivity ( kloss), and an index of “effective turnover” of dopamine ( kloss/ Ki), were obtained for both tracers during extended PET studies. 6-[18F]Fluoro-L- m-tyrosine was as effective as 6FDOPA in separating normals from MPTP-lesioned subjects on the basis of the uptake rate constants Ki and Kc. However, in contrast to 6FDOPA, it was not possible to differentiate the normal from the lesioned animal using kloss or kloss/ Ki for 6FMT. Thus, FMT appears to be a reasonable, highly specific tracer for studying the activity of aromatic dopa decarboxylase enzyme as an index of presynaptic integrity. However, if one is interested in investigating further the metabolic pathway and obtaining an in vivo estimate of the effective turnover of dopamine (after pharmacologic manipulation, for example), 6FDOPA remains the tracer of choice.

scholarly journals Measurement of Benzodiazepine Receptor Number and Affinity in Humans Using Tracer Kinetic Modeling, Positron Emission Tomography, and [11C]Flumazenil

1993 ◽  
Vol 13 (4) ◽  
pp. 656-667 ◽  
Author(s):  
Julie C. Price ◽  
Helen S. Mayberg ◽  
Robert F. Dannals ◽  
Alan A. Wilson ◽  
Hayden T. Ravert ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Specific Activity ◽  
Free Fraction ◽  
Benzodiazepine Receptor ◽  
Occipital Cortex ◽  
Compartment Model ◽  
Brain Regions ◽  
Emission Tomography ◽  
Positron Emission ◽  
Convergence Problems

Kinetic methods were used to obtain regional estimates of benzodiazepine receptor concentration ( Bmax) and equilibrium dissociation constant ( Kd) from high and low specific activity (SA) [11C]flumazenil ([11C] Ro 15-1788) positron emission tomography studies of five normal volunteers. The high and low SA data were simultaneously fit to linear and nonlinear three-compartment models, respectively. An additional inhibition study (pretreatment with 0.15 mg/kg of flumazenil) was performed on one of the volunteers, which resulted in an average gray matter K1/ k2 estimate of 0.68 ± 0.08 ml/ml (linear three-compartment model, nine brain regions). The free fraction of flumazenil in plasma ( f1) was determined for each study (high SA f1: 0.50 ± 0.03; low SA f1: 0.48 ± 0.05). The free fraction in brain ( f2) was calculated using the inhibition K1/ k2 ratio and each volunteer's mean f1 value ( f2 across volunteers = 0.72 ± 0.03 ml/ml). Three methods (Methods I–III) were examined. Method I determined five kinetic parameters simultaneously [ K1, k2, k3 (= kon f2 Bmax), k4, and kon f2/SA] with no a priori constraints. An average kon value of 0.030 ± 0.003 n M−1 min−1 was estimated for receptor-rich regions using Method I. In Methods II and III, the kon f2/SA parameter was specifically constrained using the Method I value of kon and the volunteer's values of f2 and low SA (Ci/μmol). Four parameters were determined simultaneously using Method II. In Method III, K1/ k2 was fixed to the inhibition value and only three parameters were estimated. Method I provided the most variable results and convergence problems for regions with low receptor binding. Method II provided results that were less variable but very similar to the Method I results, without convergence problems. However, the K1/ k2 ratios obtained by Method II ranged from 1.07 in the occipital cortex to 0.61 in the thalamus. Fixing the K1/ k2 ratio in Method III provided a method that was physiologically consistent with the fixed value of f2 and resulted in parameters with considerably lower variability. The average Bmax values obtained using Method III were 100 ± 25 n M in the occipital cortex, 64 ±18 n M in the cerebellum, and 38 ± 5.5 n M in the thalamus; the average Kd was 8.9 ± 1.0 n M (five brain regions).

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