In vivo quantification of monoamine oxidase A in baboon brain: a PET study using [(11)C]befloxatone and the multi-injection approach.

[(11)C]befloxatone is a high-affinity, reversible, and selective radioligand for the in vivo visualization of the monoamine oxidase A (MAO-A) binding sites using positron emission tomography (PET). The multi-injection approach was used to study in baboons the interactions between the MAO-A binding sites and [(11)C]befloxatone. The model included four compartments and seven parameters. The arterial plasma concentration, corrected for metabolites, was used as input function. The experimental protocol-three injections of labeled and/or unlabeled befloxatone-allowed the evaluation of all the model parameters from a single PET experiment. In particular, the brain regional concentrations of the MAO-A binding sites (B'(max)) and the apparent in vivo befloxatone affinity (K(d)) were estimated in vivo for the first time. A high binding site density was found in almost all the brain structures (170+/-39 and 194+/-26 pmol/mL in the frontal cortex and striata, respectively, n=5). The cerebellum presented the lowest binding site density (66+/-13 pmol/mL). Apparent affinity was found to be similar in all structures (K(d)V(R)=6.4+/-1.5 nmol/L). This study is the first PET-based estimation of the B(max) of an enzyme.

Quantification of cerebral nicotinic acetylcholine receptors by PET using 2-[18F]fluoro-A-85380 and the multiinjection approach.

The multiinjection approach was used to study in vivo interactions between alpha4beta2(*) nicotinic acetylcholine receptors and 2-[(18)F]fluoro-A-85380 in baboons. The ligand kinetics was modeled by the usual nonlinear compartment model composed of three compartments (arterial plasma, free and specifically bound ligand in tissue). Arterial blood samples were collected to generate a metabolite-corrected plasma input function. The experimental protocol, which consisted of three injections of labeled or unlabeled ligand, was aiming at identifying all parameters in one experiment. Various parameters, including B'(max) (the binding sites density) and K(d)V(R) (the apparent in vivo affinity of 2-[(18)F]fluoro-A-85380) could then be estimated in thalamus and in several receptor-poor regions. B'(max) estimate was 3.0+/-0.3 pmol/mL in thalamus, and ranged from 0.25 to 1.58 pmol/mL in extrathalamic regions. Although K(d)V(R) could be precisely estimated, the association and dissociation rate constants k(on)/V(R) and k(off) could not be identified separately. A second protocol was then used to estimate k(off) more precisely in the thalamus. Having estimated all model parameters, we performed simulations of 2-[(18)F]fluoro-A-85380 kinetics to test equilibrium hypotheses underlying simplified approaches. These showed that a pseudo-equilibrium is quickly reached between the free and bound compartments, a favorable situation to apply Logan graphical analysis. In contrast, the pseudo-equilibrium between the plasma and free compartments is only reached after several hours. The ratio of radioligand concentration in these two compartments then overestimates the true equilibrium value, an unfavorable situation to estimate distribution volumes from late images after a bolus injection.

Consensus nomenclature for in vivo imaging of reversibly binding radioligands.

An international group of experts in pharmacokinetic modeling recommends a consensus nomenclature to describe in vivo molecular imaging of reversibly binding radioligands.

Seizure-related short-term plasticity of benzodiazepine receptors in partial epilepsy: a [11C]flumazenil-PET study.

We have undertaken a test-re-test [11C]flumazenil (FMZ) PET study in 10 drug-resistant epileptic patients, including six with a mesiotemporal epilepsy (MTE), and 10 normal controls, in order to investigate seizure-related short-term plasticity of benzodiazepine (BZD) receptors. All subjects underwent two FMZ-PET scans at a 1 week interval. Patients benefited from a concurrent video-EEG monitoring which allowed determination of the duration of the interictal period (IP) preceding each PET. Test-re-test whole brain B'(max) variations, evaluated with a partial-saturation injection protocol, were similarly observed in patients and controls, suggesting a physiological modulation of BZD receptors. Five patients (50%), but no controls, also demonstrated clinically significant test-re-test FMZ-PET variations in the mesial temporal region. This was observed in all three patients with MTE and no hippocampal atrophy in whom only the PET study associated with the shortest IP correctly identified the epileptogenic zone. Statistical analysis revealed a significant effect of IP duration on BZD receptor B'(max) in MTE patients, suggesting that the shorter the IP, the lower the B'(max) in the epileptogenic hippocampus. FMZ-PET appears to be an interesting tool for investigating both normal and abnormal short-term modulations of the BZD receptor system, and should ideally be performed within a few days following a seizure in patients with MTE and a normal MRI.

Modeling [18 F]MPPF positron emission tomography kinetics for the determination of 5-hydroxytryptamine(1A) receptor concentration with multiinjection.

The selectivity of [18F]MPPF (fluorine-18-labeled 4-(2;-methoxyphenyl)-1-[2;-(N-2"-pirydynyl)-p-fluorobenzamido]ethylpiperazine) for serotonergic 5-hydroxytryptamine(1A) (5-HT1A) receptors has been established in animals and humans. The authors quantified the parameters of ligand-receptor exchanges using a double-injection protocol. After injection of a tracer and a coinjection dose of [18F]MPPF, dynamic positron emission tomography (PET) data were acquired during a 160-minute session in five healthy males. These PET and magnetic resonance imaging data were coregistered for anatomical identification. A three-compartment model was used to determine six parameters: Fv (vascular fraction), K1, k2 (plasma/free compartment exchange rate), koff, kon/Vr (association and dissociation rate), Bmax (receptor concentration), and to deduce Kd (apparent equilibrium dissociation rate). The model was fitted with regional PET kinetics and arterial input function corrected for metabolites. Analytical distribution volume and binding potential were compared with indices generated by Logan-Patlak graphical analysis. The 5HT1A specificity for MPPF was evidenced. A Bmax of 2.9 pmol/mL and a Kd of 2.8 nmol/L were found in hippocampal regions, Kd and distribution volume in the free compartment were regionally stable, and the Logan binding potential was linearly correlated to Bmax. This study confirms the value of MPPF in the investigation of normal and pathologic systems involving the limbic network and 5-HT1A receptors. Standard values can be used for the simulation of simplified protocols.

In vivo quantification and parametric images of the cardiac beta-adrenergic receptor density.

UNLABELLED: Previous studies showed that the in vivo concentration of beta-adrenergic receptor sites can be estimated by PET using (-)-4-((S)-3-tert-butylamino-2-hydroxypropoxy)-1,3-dihydrobenzoimidazol-2-one (CGP 12177), a hydrophilic ligand. A graphic method was previously proposed and used by several groups. However, this approach was not completely validated. The purpose of this study was to improve and confirm the validity of this approach through a better knowledge of the associated ligand-receptor model, estimated for the first time using the multiinjection approach. METHODS: The concentration of beta-adrenergic receptor sites was estimated for mini pigs using 2 methods. The first was the usual multiinjection approach, which permits estimation of all model parameters, including receptor concentration. However, this approach needs a complex protocol, including blood sampling, thereby making it difficult to use for studies on patients. The second method was the CGP 12177 graphic method. This approach permits the estimation of only receptor concentration but has the advantage of not requiring blood sampling. Another advantage is the ability to generate parametric images easily. RESULTS: Using the multiinjection approach, we obtained for the first time a complete model describing interactions between CGP 12177 and beta-adrenergic receptors. Knowledge of all parameters of this model permitted good validation of the assumptions included in the graphic method. The concentration of beta-adrenergic receptor sites in mini pigs was estimated at 15.2 +/- 3.4 pmol/mL. CONCLUSION: The graphic method has been improved by taking into account various phenomena, such as protein binding and the nonlinearity between plasma concentration and injected dose. This method is now usable for patient studies and offers the ability to estimate the beta-adrenergic receptor concentration from a single PET experiment without blood sampling. Parametric imaging will enable screening of the receptor site location and observation of potential anomalies in patients.