Brain kinetics and specific binding of [11C]PK 11195 to omega 3 sites in baboons: positron emission tomography study.

We characterized, in vivo, using positron emission tomography in baboons, the kinetics and specific binding of i.v. injected [¹¹C]PK 11195 to ω₃ sites in the brain. Following immediate access to brain tissue, the brain kinetics of [¹¹C]PK 11195 showed a slow elimination for the 60 min of study. Both coinjection and pulse-chase (at T = 8 min) with saturating amounts of cold PK 11195 immediately enhanced the availability of radiotracer to brain tissue, but also markedly increased the rate of washout. These effects presumably reflect displacement or inhibition of specifically bound [¹¹C]PK 11195 to both peripheral and central ω₃ sites, respectively. These results indicate that [¹¹C]PK 11195 has easy access and binds with moderate specificity to the normal primate brain in vivo.     

The role of in vivo molecular imaging with PET and SPECT in the elucidation of psychiatric drug action and new drug development

This paper reviews the contribution of human PET and SPECT neuroreceptor occupancy studies to the understanding of drug action in psychiatric illness, and how they can aid the development of new drugs. All effective antipsychotics show significant D₂ receptor occupancy. However, at least for atypical antipsychotics, there is no clear relationship between occupancy and clinical response. The mechanisms underlying antipsychotic efficacy, and the minimal effective D₂ occupancy, remain to be elucidated, particularly for drugs with modest or transient occupancy. The low liability of some atypical antipsychotics for extrapyramidal side effects does not appear to be explained by their 5-HT_2A antagonism, and the muscarinic receptor occupancy of some drugs may be partly explanatory. Previous reports of apparent ‘limbic selectivity’ of atypical antipsychotics may be in error, and may be due to technical differences in radiotracers. For SSRIs, high occupancies at the serotonin transporter (SERT) are achieved at therapeutic doses, although the minimum SERT occupancy required for therapeutic response remains undefined. Previous attempts to augment the antidepressant effect of SSRIs by pindolol have generally used daily doses which result in inadequate 5-HT_1A receptor occupancy. For benzodiazepines, clinical doses would appear to leave a wide margin of unoccupied receptors. For methylphenidate and cocaine, typical doses occupy more than 50% of dopamine transporters, and their profiles are extremely similar. In therapeutic drug development, these techniques may be used to assess receptor occupancy profiles, likely drug dosages and dosing intervals which cannot be reliably assessed in humans by other methods.     

Brain 5-HT2A receptor occupancy of deramciclane in humans after a single oral administration – a positron emission tomography study

Rationale: Deramciclane fumarate is a new 5-HT_2A and 5-HT_2C receptor antagonist with putative anxiolytic effects. In the present study the binding of deramciclane to serotonin 5-HT_2A receptors in frontal cortex of healthy male volunteers was studied using [¹¹C]-N-methyl spiperone ([¹¹C]-NMSP) and positron emission tomography. Methods: The receptor occupancy percentage was assessed by the means of inhibition of [¹¹C]-NMSP from the 5-HT_2A receptors in the frontal cortex. Single oral doses of 20, 50 and 150 mg deramciclane were given to three subjects at each dose level (total n = 9). The receptor occupancy was measured before deramciclane and at 3 and 6 h post-dosing except at the 20 mg dose level where only the 3-h measurement was done. The occupancy percentage was calculated with the ratio method using cerebellum as a reference area. Results: Deramciclane inhibited [¹¹C]-NMSP binding dose and concentration dependently. However, deramasciclane inhibited maximally only 52% of the [¹¹C]-NMSP binding in the frontal cortex, indicating a non-5-HT_2A receptor binding component of this radioligand in frontal cortex. On average, specific [¹¹C]-NMSP binding cerebellum ratios below 0.355 were not possible to achieve in this population. The 52% inhibition was regarded to represent near 100% 5-HT_2A receptor occupancy. The 50 and 90% receptor occupancies were reached at deramciclane plasma concentrations of 21 ng/ml and 70 ng/ml, respectively. Conclusions: Deramciclane penetrates the blood-brain barrier in humans. Deramciclane binds to the 5-HT_2A receptors in the frontal cortex in a saturable manner in vivo. Consequently, the increase in deramciclane concentration in plasma above 70 ng/ml will not result in major increase in the 5-HT_2A receptor occupancy in the brain. Received: 7 September 1998/Final version: 11 January 1999     

A PET-study of [11C]FLB 457 binding to extrastriatal D2-dopamine receptors in healthy subjects and antipsychotic drug-treated patients

We recently developed [¹¹C]FLB 457 a substituted benzamide with the very high affinity of 20 pM for D₂-dopamine receptors in vitro. The aim of the present exploratory study was to examine the anatomical distribution of [¹¹C]FLB 457 binding in the human brain and to determine extrastriatal D₂-receptor occupancy in antipsychotic drug-treated patients. [¹¹C]raclopride was used to obtain reference values for D₂-dopamine receptor occupancy in the putamen. After IV injection of [¹¹C]FLB 457 there was a high concentration of radioactivity, not only in the caudate putamen but also in the thalamus and the temporal cortex. The concentration of radioactivity in the frontal cortex, the substantia nigra and the colliculi was slightly higher than in the cerebellum. Pretreatment with haloperidol and fluphenazine indicated that [¹¹C]FLB 457 binding in extrastriatal regions to a high degree represents specific binding to D₂-dopamine receptors. The D₂-occupancy in antipsychotic drug-treated patients was on the same level in the thalamus and the temporal cortex as that determined with [¹¹C]raclopride in the putamen. The study shows that [¹¹C]FLB 457 has potential for quantitative PET-examination of D₂-dopamine receptors in man. Received: 24 March 1997 /Final version: 5 May 1997     

Evaluation and improvement of CuI-mediated 11C-cyanation

CuI-mediated ¹¹C-cyanation was evaluated by synthesizing [¹¹C]perampanel ([¹¹C] 5 ) as a model compound and compared with previous reports. To a DMF solution with 5′-(2-bromophenyl)-1′-phenyl-[2,3′-bipyridin]-6′(1′H)-one ( 4 ) and CuI, [¹¹C]NH₄CN in a stream of ammonia/nitrogen (5:95, v/v) gas was bubbled. Subsequently, the reaction mixture was heated at 180°C for 5 min. After HPLC purification, [¹¹C] 5 was obtained in 7.2 ± 1.0% (n = 4) non-decay corrected radiochemical yield with >99% radiochemical purity and a molar activity of 98 ± 28 GBq/μmol. In vivo evaluations of [¹¹C] 5 were performed using small animals. PET scans to check the kinetics of [¹¹C] 5 in the whole body of mice suggested that [¹¹C] 5 spreads rapidly into the brain, heart, and lungs and then accumulates in the small intestine. To evaluate the performance of CuI-mediated ¹¹C-cyanation reaction, bromobenzene ( 6a ) was selected as the model compound; however, it failed. Therefore, optimization of the reaction conditions has been performed, and consequently, the addition of K₂CO₃ and prolonging the reaction time improved the radiochemical yield about double. With this improved method, CuI-mediated ¹¹C-cyanation of various (hetero)aromatic bromides was performed to exhibit the tolerance of most functional groups and to provide ¹¹C-cyanated products in good to moderate radiochemical yields.     

Positron emission tomographic analysis of dose-dependent NAD-299 binding to 5-hydroxytryptamine-1A receptors in the human brain

Rationale. The serotonin 5-HT_1A receptor has been ascribed a putative role in the pathophysiology and drug treatment of depression. NAD-299 (generic name robalzotan) is a new potential antidepressant with high affinity and selectivity for the 5-HT_1A receptor. Objectives. The aim of this positron emission tomography (PET) study was to examine the extent and time-course of 5-HT_1A occupancy by NAD-299 in the human brain, in relation to plasma concentration after escalating single oral doses. Methods. Five healthy male subjects received one or more single oral doses of NAD-299 (0.5, 2.5 and 10 mg) in aqueous solution under fasting conditions. Total and unbound (after ultrafiltration) plasma concentrations of NAD-299 were determined by liquid chromatography-mass spectrometry (LC-MC), over a tentative dosage interval of 8 h. Regional 5-HT_1A receptor occupancy in brain was calculated by the simplified reference tissue model using the radioligand [carbonyl-¹¹C]WAY-100635. Results. After the 10 mg dose, occupancy was high in the raphe (62–85%) and neocortical regions (68–75%) at time for C_max, but had declined considerably (17–44%) at 7 h after dose intake. Conclusions. This study confirmed that the new selective 5-HT_1A antagonist NAD-299 occupies 5-HT_1A receptors in the living human brain in a dose-dependent manner following oral dosage. The curvilinear relationship between NAD-299 drug concentration and 5-HT_1A receptor occupancy was established and can be used for dose selection in subsequent clinical patient studies. Electronic Publication     

Synthesis of MMP inhibitor radiotracer [11C]CGS 25966, a new potential pet tumor imaging agent

[¹¹C]CGS 25966, a novel radiolabeled matrix metalloproteinase (MMP) inhibitor, has been synthesized for evaluation as new potential positron emission tomography (PET) tumor imaging agent. The precursor was labeled by [¹¹C]methyl triflate through O‐[¹¹C]methylation method at the hydroxyl position of phenol under basic conditions and isolated by HPLC purification to produce pure target compound in 15–25% radiochemical yield, based on ¹¹CO₂, decay corrected to end of bombardment. Copyright © 2003 John Wiley & Sons, Ltd.     

Radioligand studies: imaging and quantitative analysis

Radioligand studies enable visualisation and measurement of molecular pathways and pharmacokinetic processes. Using positron emission tomography, accurate measurements of the time course of radioligand uptake and clearance can be obtained. A tracer kinetic model is needed to derive physiological or pharmacokinetic parameters from these tissue time-activity curves. In addition, an input function that indicates delivery to the tissue is required. Usually this will be the arterial plasma curve. For receptor studies, where binding potential is the parameter of interest, it might also be possible to avoid arterial sampling provided a tissue can be defined that is devoid of receptors.     

Imaging the peripheral benzodiazepine receptor response in central nervous system demyelination and remyelination.

We used a rodent model of cuprizone-induced demyelination to examine the peripheral benzodiazepine receptor (PBR) response during remyelination. C57BL/6J mice were fed a 0.2% cuprizone-containing or control diet for 3 weeks and then removed to allow for remyelination. Quantitative autoradiography of 3H-(R)-PK11195 binding to PBR in the corpus callosum showed increased levels at 3 weeks of demyelination and gradually decreased as a function of remyelination. PBR levels were associated with the degree of remyelination and activation of microglia and astrocytes. However, the temporal pattern suggests that the PBR signal during the late stages of remyelination was primarily associated with astrocytes. We also used small-animal positron-emission tomography (PET) imaging to determine if this technique could be used to monitor PBR levels in the brain of living mice. The results indicate that 11C-(R)-PK11195 levels are significantly elevated in the mouse brain during cuprizone-induced demyelination and normalize at a time in which remyelination is complete. These findings support the notion that PBR is a sensitive marker for the visualization and quantification of brain injury and recovery. Further, the in vivo imaging of the PBR response is now possible in the living rodent brain.     

Radiosynthesis of 1‐iodo‐2‐[11C]methylpropane and 2‐methyl‐1‐[11C]propanol and its application for alkylation reactions and C―C bond formation

The multitude of biologically active compounds requires the availability of a broad spectrum of radiolabeled synthons for the development of positron emission tomography (PET) tracers. The aim of this study was to synthesize 1‐iodo‐2‐[¹¹C]methylpropane and 2‐methyl‐1‐[¹¹C]propanol and investigate the use of these reagents in further radiosynthesis reactions. 2‐Methyl‐1‐[¹¹C]propanol was obtained with an average radiochemical yield of 46 ± 6% d.c. and used with fluorobenzene as starting material. High conversion rates of 85 ± 4% d.c. could be observed with HPLC, but large precursor amounts (32 mg, 333 μmol) were needed. 1‐Iodo‐2‐[¹¹C]methylpropane was synthesized with a radiochemical yield of 25 ± 7% d.c. and with a radiochemical purity of 78 ± 7% d.c. The labelling agent 1‐iodo‐2‐[¹¹C]methylpropane was coupled to thiophenol, phenol and phenylmagnesium bromide. Average radiochemical conversions of 83% d.c. for thiophenol, 40% d.c. for phenol, and 60% d.c. for phenylmagnesium bromide were obtained. In addition, [¹¹C]2‐methyl‐1‐propyl phenyl sulphide was isolated with a radiochemical yield of 5 ± 1% d.c. and a molar activity of 346 ± 113 GBq/μmol at the end of synthesis. Altogether, the syntheses of 1‐iodo‐2‐[¹¹C]methylpropane and 2‐methyl‐1‐[¹¹C]propanol were achieved and applied as proof of their applicability.     

Synthesis of MMP inhibitor radiotracers [11C]methyl‐CGS 27023A and its analogs,new potential PET breast cancer imaging agents

[¹¹C]Methyl‐CGS 27023A ( 1a ) and its analogs [¹¹C]methyl‐2‐picolyl‐CGS 27023A ( 1b ), [¹¹C]methyl‐benzyl‐CGS 27023A ( 1c ), [¹¹C]methyl‐2‐nitro‐CGS 27023A ( 1d ), [¹¹C]methyl‐3‐nitro‐CGS 27023A ( 1e ), and [¹¹C]methyl‐4‐nitro‐CGS 27023A ( 1f ), novel radiolabeled matrix metalloproteinase (MMP) inhibitors, have been synthesized for evaluation as new potential positron emission tomography (PET) breast cancer imaging agents. The appropriate precursors for radiolabeling were obtained in four to five steps from starting material amino acid D ‐valine with moderate to excellent chemical yields. Precursors were labeled by [¹¹C]methyl triflate through ¹¹C–O‐methylation method at the aminohydroxyl position under basic conditions and isolated by solid‐phase extraction (SPE) purification to produce pure target compounds in 40–60% radiochemical yields (decay corrected to end of bombardment), in 20–25 min synthesis time. Copyright © 2002 John Wiley & Sons, Ltd.     

Use of positron emission tomography in analysing receptor function in vivo

The non-invasive radiotracer technique positron emission tomography (PET) may provide valuable information in the toxicokinetic–toxicodynamic evaluation of endogenous or toxic environmental compounds. Assessment of mechanism of action of toxins is often difficult to validate. In this respect, PET may offer advantages since it can quantify not only the distribution and kinetics of the radiolabelled toxin in the body, but also the altered rates of physiological or biochemical processes induced by the toxin. It is even possible to validate the body distribution and tissue accumulation of the toxic compound in primates, since linear kinetics can be assumed after administration of the radiolabelled compound in minute amounts without any toxic or physiological effects. Quantitative estimates can be derived with accuracy and high precision. Using a multi-tracer protocol, it is often possible to illuminate both the kinetics and the dynamics of a toxic compound. Long-term effects of different toxins on dopamine receptor function have been evaluated with PET as well as the influence of Parkinson disease medication on pre- and postsynaptic dopaminergic receptor function over the course of the disease. In conclusion, PET may provide very informative insight into complex receptor interactions of both toxic compounds and drugs under development.     

Developments in whole-body molecular imaging of live subjects

New molecular imaging technologies are being developed specifically for imaging animal models of human disease. Positron emission tomography (PET) in particular allows in vivo biochemistry to be studied with a high degree of sensitivity and specificity, and provides direct in vivo information on molecular and cellular pathways that underlie disease mechanisms and therapeutics. However, clinical PET systems have inadequate resolution for imaging small animals. Thus, specialized high-resolution PET hardware and software are now being developed.     

A PET study of D1-like dopamine receptor ligand binding

Rationale: Several positron emission tomography (PET) studies have shown that radioligand binding to D₂-like dopamine receptors competes with endogenous dopamine. Objective: The purpose of this PET study was to examine the effect of amphetamine and reserpine on D₁-like dopamine receptor binding. Methods: Three Cynomolgus monkeys were examined with the radioligands [¹¹C]SCH 23390 or [¹¹C]NNC 112 at baseline condition and after pretreatment with amphetamine (2 mg/kg IV). The B/F values (binding potential) in the striatum and the neocortex were calculated at transient equilibrium. In two monkeys, the effect of the long-lasting dopamine depletion after reserpine (1 mg/kg IV) was followed by a repeated Scatchard procedure in up to 77 days after drug administration. The Scatchard analysis was based on two PET measurements with high and low specific radioactivity and allowed the calculation of D₁-like dopamine receptor density (B_max) and apparent affinity (K_D ^app). Results: The effect of amphetamine on the B/F values was between –14 and 6%. These changes can be considered as within the range of the test-retest reliability. Thus, there was no evident effect of amphetamine-induced dopamine release on D₁-like dopamine receptor binding. Five hours after reserpine administration, there was no change in B_max or K_D ^app. At 3, 23, and 28 days after reserpine administration, the Scatchard analyses indicated a 13–20% reduction in B_max without any evident change in K_D ^app in both the striatum and the neocortex. Conclusions: The lack of evident effects of amphetamine and reserpine on D₁-like dopamine receptor binding is markedly different from the 20% amphetamine-induced decrease and 50% reserpine-induced increase that has been consistently reported for D₂-like dopamine receptor binding. The data indicated that D₁-like dopamine receptor occupancy of endogenous dopamine is low at physiological condition. It is thus unlikely that D₁-like dopamine receptor radioligands can be used to measure changes in the concentration of endogenous dopamine. Received: 8 March 1999 / Final version: 12 May 1999     

^18F-脱氧葡萄糖正电子发射断层显像-X线计算机断层显像误诊分析

目的探讨^18F-脱氧葡萄糖正电子发射断层显像-X线计算机断层显像（FDGPET／CT）肿瘤显像与误诊原因。方法分析3例^18F-FDGPET／CT误诊为恶性肿瘤的临床资料并复习相关文献。结果全身^18F-FDGPET／CT显像在恶性肿瘤诊断、分期、疗效评价和预后判断等方面有明确的临床价值,但炎症、结核是最常见的非肿瘤性浓聚原因,常导致临床误诊。结论^18F-FDGPET／CT对恶性肿瘤的诊断有一定的价值,但易出现假阳性,特别是炎症、结核较为常见。因此,临床工作中,对恶性肿瘤的诊断应谨慎结论。     

In vivo visualization of donepezil binding in the brain of patients with Alzheimer's disease

Aims

The aims of this study were to visualize in vivo binding of donepezil to acetylcholinesterase (AChE) in the brain and to establish a method for measuring the amount of binding of orally administered donepezil.

Methods

[5-¹¹C-methoxy]-donepezil ([¹¹C]-donepezil) was radiolabelled as a positron emission tomography (PET) tracer. The biodistribution of [¹¹C]-donepezil was measured by PET in 10 AD patients and six elderly normal subjects. Two AD patients underwent additional PET measurements after oral administration of donepezil for 6 months.

Results

[¹¹C]-donepezil-PET images demonstrated high densities of tracer distribution in AChE-rich brain regions such as the striatum, thalamus, and cerebellum. Compared with elderly normal subjects, patients with mild AD exhibited about 18–20% reduction of donepezil binding in the neocortex and hippocampus, while patients with moderate AD exhibited about 24–30% reduction of donepezil binding throughout the brain. Orally administered donepezil (5 mg day⁻¹) induced 61.6–63.3% reduction of donepezil binding in AD brains. The distribution volume of [¹¹C]-donepezil in the hippocampus was significantly correlated with MMSE scores in AD patients.

Conclusions

[¹¹C]-donepezil-PET enables quantitative measurement of donepezil binding in the brain. AD patients exhibited reduction of donepezil binding in the brain, even in the early stage of disease. Longitudinal evaluation by this technique enables determination of AChE binding occupancy of orally administered donepezil.

What is already known about this subject

• Deficit in central cholinergic neurotransmission is a consistent change associated with Alzheimer''s disease (AD).
• Donepezil hydrochloride exhibits selective inhibition of acetylcholinesterase (AChE) and is widely used for the treatment of AD.
• The biodistribution of donepezil in the brain after administration is not precisely understood in vivo.
• There is no method to measure the amount of binding of orally administered donepezil to AChE.

What this study adds

• This study clearly visualizes the distribution of donepezil in human brain using [¹¹C]-donepezil and positron emission tomography.
• This study demonstrates prominent reduction of the donepezil binding site in the AD brain.
• This study provides methodology to measure the AChE binding occupancy of orally administered donepezil and provides a new surrogate marker for evaluation and prediction of response to donepezil treatment.

     

恶性胸膜间皮瘤的影像学诊断

恶性胸膜间皮瘤（MPM）是起源于胸膜间皮细胞一种罕见肿瘤，该病无典型表现，恶性程度较高，预后较差。影像学检查在MPM的诊断、分期及病情评估中起重要作用。现就恶性胸膜间皮瘤的影像学表现，以及各种影像学检查方法对恶性胸膜间皮瘤诊断、分期、预后判断的价值作一综述。     

Leveraging Open Science Drug Development for PET: Preliminary Neuroimaging of 11C-Labeled ALK2 Inhibitors

Mutations in the gene encoding activin receptor-like kinase 2 (ALK2) are implicated in the pathophysiology of a pediatric brainstem cancer, diffuse intrinsic pontine glioma (DIPG). Inhibitors of ALK2 that cross the blood–brain barrier have been proposed as a method of treatment for DIPG. As part of an open science approach to radiopharmaceutical and drug discovery, we developed ¹¹C-labeled radiotracers from potent and selective lead ALK2 inhibitors to investigate their brain permeability through positron emission tomography (PET) neuroimaging. Four radiotracers were synthesized by ¹¹C-methylation and assessed by dynamic PET imaging in healthy Sprague–Dawley rats. One of the compounds, [¹¹C]M4K2127, showed high initial brain uptake (SUV ∼ 2), including in the region of interest (pons). This data supports the use of this chemotype as a brain penetrant ALK2 inhibitor that permeates evenly into the pons with potential application for the treatment of DIPG.     

Salvinorin A and derivatives: Protection from metabolism does not prolong short-term, whole-brain residence

Salvinorin A (SA) is a potent kappa opioid agonist with a brief duration of action. Consistent with this, our previous positron emission tomography (PET) studies of carbon-11 labeled SA showed that brain levels decrease rapidly after intravenous administration. SA is rapidly metabolized, giving the much less potent salvinorin B (SB), which is presumed to be responsible in part for SA's brief duration of action. To test this, we labeled the metabolically stable methyl ester of SA and SB with carbon-11 and compared their pharmacokinetics by PET imaging after intravenous administration to baboons. Labeling of salvinorin B ethoxymethyl ether (EOM-SB), a derivative with greater potency and resistance to metabolism, provided an additional test of the role of metabolism in brain efflux. Plasma analysis confirmed that SB and EOM-SB exhibited greater metabolic stability than SA. However, the three compounds exhibited very similar pharmacokinetics in brain, entering and exiting rapidly. This suggests that metabolism is not solely responsible for the brief brain residence time of SA. We determined that whole-brain concentrations of EOM-SB declined more slowly than SA after intraperitoneal administration in rodents. This is likely due to a combination in EOM-SB's increased metabolic stability and its decreased plasma protein affinity. Our results suggest that protecting salvinorin A derivatives from metabolism will prolong duration of action, but only when administered by routes giving slow absorption.     

Striatal D2 dopamine receptor binding characteristics in vivo in patients with alcohol dependence

Striatal D₂ dopamine receptor characteristics of nine male patients with alcohol dependence abstinent for 1–68 weeks and eight healthy male volunteers were studied in vivo with positron emission tomography. The selective D₂ receptor ligand [¹¹C]raclopride and equilibrium model was used for D₂ receptor density (B_max) and affinity (K_d) measurements. A trend for a decreased striatal D₂ receptor density and for reduced D₂ receptor affinity was observed in patients with alcohol dependence. These parameters were not statistically significantly different between alcoholics and controls, but the ratio between D₂ receptor density and affinity (B_max/K_d or the striatum/cerebellum ratio from the high specific activity scan) was highly significantly lower in alcoholics than that of controls. In conclusion, the low D₂ dopamine receptor B_max/K_d ratio (striatum/cerebellum ratio) indicates that specific aspects of striatal [¹¹C]raclopride binding in vivo are deviant in alcoholics compared to controls. The result is compatible with a reduced avidity of striatal dopamine D₂ receptors in alcoholics, which is in line with the idea that D₂ dopaminergic mechanisms are involved in the biology of alcohol dependence in man.