Radioligand In Plasma Research Articles

In vitro and in vivo Human Metabolism of (S)-[18F]Fluspidine – A Radioligand for Imaging σ1 Receptors With Positron Emission Tomography (PET)

(S)-[18F]fluspidine ((S)-[18F]1) has recently been explored for positron emission tomography (PET) imaging of sigma-1 receptors in humans. In the current report, we have used plasma samples of healthy volunteers to investigate the radiometabolites of (S)-[18F]1 and elucidate their structures with LC-MS/MS. For the latter purpose additional in vitro studies were conducted by incubation of (S)-[18F]1 and (S)-1 with human liver microsomes (HLM). In vitro metabolites were characterized by interpretation of MS/MS fragmentation patterns from collision-induced dissociation or by use of reference compounds. Thereby, structures of corresponding radio-HPLC-detected radiometabolites, both in vitro and in vivo (human), could be identified. By incubation with HLM, mainly debenzylation and hydroxylation occurred, beside further mono- and di-oxygenations. The product hydroxylated at the fluoroethyl side chain was glucuronidated. Plasma samples (10, 20, 30 min p.i., n = 5-6), obtained from human subjects receiving 250–300 MBq (S)-[18F]1 showed 97.2, 95.4, and 91.0% of unchanged radioligand, respectively. In urine samples (90 min p.i.) the fraction of unchanged radioligand was only 2.6% and three major radiometabolites were detected. The one with the highest percentage, also found in plasma, matched the glucuronide formed in vitro. Only a small amount of debenzylated metabolite was detected. In conclusion, our metabolic study, in particular the high fractions of unchanged radioligand in plasma, confirms the suitability of (S)-[18F]1 as PET radioligand for sigma-1 receptor imaging.

Quantification of PET infusion studies without true equilibrium: A tissue clearance correction

In some positron emission tomography (PET) studies, a reversibly binding radioligand is administered as a constant infusion to establish true equilibrium for quantification. This approach reduces scanning time and simplifies data analysis, but assumes similar behavior of the radioligand in plasma across the study population to establish true equilibrium in all subjects. Bias in outcome measurements can result if this assumption is not met. This work developed and validated a correction that reduces bias in total distribution volume (VT) estimates when true equilibrium is not present. This correction, termed tissue clearance correction (TCC), took the form , where β is the radioligand clearance rate in tissue, γ is a radiotracer-specific constant, and VT(A) is the apparent VT. Simulations characterized the robustness of TCC across imperfect values of γ and β and demonstrated reduction to false positive rates. This approach was validated with human infusion data for three radiotracers: [18F]FPEB, (−)-[18F]flubatine, and [11C]UCB-J. TCC reduced bias in VT estimates for all radiotracers and significantly reduced intersubject variance in VT for [18F]FPEB data in some brain regions. Thus, TCC improves quantification of data acquired from PET infusion studies.

Radioligand binding analysis of \u03b12 adrenoceptors with [11C]yohimbine in brain in vivo: Extended Inhibition Plot correction for plasma protein binding

We describe a novel method of kinetic analysis of radioligand binding to neuroreceptors in brain in vivo, here applied to noradrenaline receptors in rat brain. The method uses positron emission tomography (PET) of [11C]yohimbine binding in brain to quantify the density and affinity of α2 adrenoceptors under condition of changing radioligand binding to plasma proteins. We obtained dynamic PET recordings from brain of Spraque Dawley rats at baseline, followed by pharmacological challenge with unlabeled yohimbine (0.3 mg/kg). The challenge with unlabeled ligand failed to diminish radioligand accumulation in brain tissue, due to the blocking of radioligand binding to plasma proteins that elevated the free fractions of the radioligand in plasma. We devised a method that graphically resolved the masking of unlabeled ligand binding by the increase of radioligand free fractions in plasma. The Extended Inhibition Plot introduced here yielded an estimate of the volume of distribution of non-displaceable ligand in brain tissue that increased with the increase of the free fraction of the radioligand in plasma. The resulting binding potentials of the radioligand declined by 50–60% in the presence of unlabeled ligand. The kinetic unmasking of inhibited binding reflected in the increase of the reference volume of distribution yielded estimates of receptor saturation consistent with the binding of unlabeled ligand.

Radiolabelling and preliminary evaluation of 68Ga-tetrapyrrole derivatives as potential tracers for PET

Tetrapyrroles are multisided natural products which are of relevance in clinical medicine. Owing to their specific accumulation in tumour tissue, porphyrins, metalloporphyrins and chlorins have been used as in photodynamic therapy and optical imaging. Moreover, their specific uptake into inflammatory atheromatous plaques via LDL endocytosis has been reported. The present study is concerned with the synthesis of (68)Ga labelled porphyrin derivatives and an in vitro assessment of the utility of radiotracers in positron emission tomography. A set of five porphyrin derivatives were labelled using (68)Ga from a commercially obtained radionuclide generator. Dedicated post-processing of the generator eluate was conducted to allow for labelling in aqueous media and also under anhydrous conditions. Challenge studies and incubation in human serum confirmed the stability of the tracers. Plasma protein binding was investigated in order to confirm the presence of freely diffusible radioligand in plasma. A preliminary microPET study in a tumour-bearing rat resulted in a clear visualisation of the tumour.

Imaging of the Striatal and Extrastriatal Dopamine Transporter with 18F-LBT-999: Quantification, Biodistribution, and Radiation Dosimetry in Nonhuman Primates

The aim of this study was to evaluate the quantification, biodistribution, and radiation dosimetry of the novel dopamine transporter (DAT) radioligand (18)F-(2S,3S)-methyl 8-((E)-4-fluorobut-2-en-1-yl)-3-(p-tolyl)-8-azabicyclo[3.2.1]octane-2-carboxylate ((18)F-LBT-999) in nonhuman primates. The brain study was conducted in 4 female rhesus monkeys. PET measurements were conducted for 243 min using the high-resolution research tomograph (HRRT) with the measurement of the metabolite-corrected arterial input function and protein binding. Quantification was performed with kinetic analysis using 2-tissue- and 1-tissue-compartment models, with Logan graphical analysis and with different reference tissue models. The outcome measures were total distribution volume (V(T)), nondisplaceable distribution volume (V(ND)), binding potential relative to the free concentration of radioligand in plasma (BP(F)), and binding potential relative to the concentration of nondisplaceable radioligand in tissue (BP(ND)) = V(T) - V(ND)/V(ND) using the cerebellum as a reference region. For the biodistribution and radiation dosimetry, 2 female cynomolgus monkeys were studied. Whole-body PET scans were obtained using a PET/CT system for approximately 250 min. Estimates of the absorbed radiation dose in humans were calculated using OLINDA/EXM software. (18)F-LBT-999 showed good brain uptake (300% standardized uptake value) and regional distribution according to known DAT density. The 2-tissue-compartment model was the preferred model for the quantification. Late peak equilibrium (120-140 min) and slow washout were observed in the striatum, with high variability of V(T), BP(F), and BP(ND). When the different models were compared with the 2-tissue-compartment model, the underestimation of V(T) or BP(ND) was larger in the caudate and putamen than in the midbrain and thalamus. The reference tissue models were suitable for the quantification. The whole-body distribution study showed that the main routes of excretion of (18)F-LBT-999 were the urinary and gastrointestinal systems, with the bladder being the critical organ. Accumulation of (18)F-LBT-999 was found in the bone and skull, with a relatively high dose estimated for the osteogenic cells. The range of calculated effective dose was 0.021-0.022 mSv/MBq. (18)F-LBT-999 seemed to be a suitable PET radioligand for the DAT quantification, particularly for extrastriatal regions. The skull uptake did not seem to be a limitation for brain imaging. The calculated dosimetry estimates based on data in nonhuman primates seemed comparable with those of other clinically used (18)F-labeled radioligands, for example, (18)F-FDG (0.024-0.027 mSv/MBq).

Quantitative Analysis of [11C]AZ10419369 Binding to 5-HT1B Receptors in Human Brain

A novel radioligand for positron emission tomography (PET) imaging of serotonin 5-HT(1B) receptors, [(11)C]AZ10419369, has been recently described. In this study, the potential for quantitative analysis of [(11)C]AZ10419369 binding to central 5-HT(1B) receptors was evaluated in human subjects. PET measurements were performed after injection of [(11)C]AZ10419369 in 10 subjects. Data were analyzed with kinetic modeling and linear graphical analysis using the arterial plasma as input function, and with reference tissue models using cerebellar cortex as the reference region. Binding of [(11)C]AZ10419369 was highest in pallidum, ventral striatum, and occipital cortex and lowest in cerebellum. The percentage of unchanged radioligand in plasma was 97% to 99%, indicating that no significant amounts of radioactive metabolites were formed during the time of analysis. Time-activity curves of [(11)C]AZ10419369 could be described with both one-tissue compartment (1-TC) and two-tissue compartment (2-TC) models in the majority of subjects. The 2-TC model failed to deliver reasonable estimates of the kinetic parameters. However, stable estimates of binding potential (BP(ND)) were obtained by constraining K(1)/k(2) to the distribution volume obtained with the 1-TC model in the cerebellar cortex. BP(ND) values estimated with reference tissue models were correlated with the corresponding values obtained with kinetic modeling. The findings support the use of reference tissue models in applied clinical studies with [(11)C]AZ10419369.

Approaches to quantify radioligands that wash out slowly from target organs

Approaches to quantify radioligands that wash out slowly from target organs

Imaging and Quantitation of Cannabinoid CB1 Receptors in Human and Monkey Brains Using 18F-Labeled Inverse Agonist Radioligands

We recently demonstrated that (11)C-MePPEP, a PET ligand for CB(1) receptors, has such high uptake in the human brain that it can be imaged for 210 min and that receptor density can be quantified as distribution volume (V(T)) using the gold standard of compartmental modeling. However, (11)C-MePPEP had relatively poor retest and intersubject variabilities, which were likely caused by errors in the measurements of radioligand in plasma at low concentrations by 120 min. We sought to find an analog of (11)C-MePPEP that would provide more accurate plasma measurements. We evaluated several promising analogs in the monkey brain and chose the (18)F-di-deutero fluoromethoxy analog ((18)F-FMPEP-d(2)) to evaluate further in the human brain. (11)C-FMePPEP, (18)F-FEPEP, (18)F-FMPEP, and (18)F-FMPEP-d(2) were studied in 5 monkeys with 10 PET scans. We calculated V(T) using compartmental modeling with serial measurements of unchanged parent radioligand in arterial plasma and radioactivity in the brain. Nonspecific binding was determined by administering a receptor-saturating dose of rimonabant, an inverse agonist at the CB(1) receptor. Nine healthy human subjects participated in 17 PET scans using (18)F-FMPEP-d(2), with 8 subjects having 2 PET scans to assess retest variability. To identify sources of error, we compared intersubject and retest variability of brain uptake, arterial plasma measurements, and V(T). (18)F-FMPEP-d(2) had high uptake in the monkey brain, with greater than 80% specific binding, and yielded less radioactivity uptake in bone than did (18)F-FMPEP. High brain uptake with (18)F-FMPEP-d(2) was also observed in humans, in whom V(T) was well identified within approximately 60 min. Retest variability of plasma measurements was good (16%); consequently, V(T) had a good retest variability (14%), intersubject variability (26%), and intraclass correlation coefficient (0.89). V(T) increased after 120 min, suggesting an accumulation of radiometabolites in the brain. Radioactivity accumulated in the skull throughout the entire scan but was thought to be an insignificant source of data contamination. Studies in monkeys facilitated our development and selection of (18)F-FMPEP-d(2), compared with (18)F-FMPEP, as a radioligand demonstrating high brain uptake, high percentage of specific binding, and reduced uptake in bone. Retest analysis in human subjects showed that (18)F-FMPEP-d(2) has greater precision and accuracy than (11)C-MePPEP, allowing smaller sample sizes to detect a significant difference between groups.

Quantification of Translocator Protein (18 kDa) in the Human Brain with PET and a Novel Radioligand, 18F-PBR06

Translocator protein (TSPO) (18 kDa), formerly called the peripheral benzodiazepine receptor, is upregulated on activated microglia and macrophages and is, thus, a biomarker of inflammation. We previously reported that an (11)C-labeled aryloxyanilide (half-life, 20 min) was able to quantify TSPOs in the healthy human brain. Because many PET centers would benefit from a longer-lived (18)F-labeled radioligand (half-life, 110 min), the objective of this study was to evaluate the ability of a closely related aryloxyanilide ((18)F-N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline [(18)F-PBR06]) to quantify TSPOs in the healthy human brain. A total of 9 human subjects were injected with (18)F-PBR06 (approximately 185 MBq) and scanned for 5 h, with rest periods outside the camera. The concentrations of (18)F-PBR06, separated from radiometabolites, were measured in arterial plasma. Modeling of regional brain and plasma data showed that a 2-tissue-compartment model was superior to a 1-tissue-compartment model. Even if data for all time points were used for the fitting, concentrations of brain activity measured with PET were consistently greater than the modeled values at late (280-300 min) but not at early time points. The greater values may have been caused by the slow accumulation of radiometabolites in the brain. To determine an adequate time for more accurate measurement of distribution volume (V(T)), which is the summation of receptor binding and nondisplaceable activity, we investigated which scan duration would be associated with maximal or near-maximal identifiability. We found that a scan of 120 min provided the best identifiability of V(T) (approximately 2%). The images showed no significant defluorination. (18)F-PBR06 can quantify TSPOs in the healthy human brain using 120 min of image acquisition and concurrent measurements of radioligand in plasma. Although brain activity is likely contaminated with radiometabolites, the percentage contamination is thought to be small (<10%), because values of distribution volume are stable during 60-120 min and vary by less than 10%. (18)F-PBR06 is a longer-lived and promising alternative to (11)C-labeled radioligands to measure TSPOs as a biomarker of inflammation in the brain.

Species Differences in Blood-Brain Barrier Transport of Three Positron Emission Tomography Radioligands with Emphasis on P-Glycoprotein Transport

Species differences occur in the brain concentrations of drugs, but the reasons for these differences are not yet apparent. This study was designed to compare brain uptake of three radiolabeled P-glycoprotein (P-gp) substrates across species using positron emission tomography. Brain concentrations and brain-to-plasma ratios were compared; [(11)C]verapamil in rats, guinea pigs, and monkeys; [(11)C](S)-(2-methoxy-5-(5-trifluoromethyltetrazol-1-yl)-phenylmethylamino)-2(S)-phenylpiperidine (GR205171) in rats, guinea pigs, monkeys, and humans; and [(18)F]altanserin in rats, minipigs, and humans. The fraction of the unbound radioligand in plasma was studied along with its metabolism. The effect of P-gp inhibition was investigated by administering cyclosporin A (CsA). Pronounced species differences were found in the brain and brain-to-plasma concentrations of [(11)C]verapamil, [(11)C]GR205171, and [(18)F]altanserin with higher brain distribution in humans, monkeys, and minipigs than in rats and guinea pigs. For example, the brain-to-plasma ratio of [(11)C]GR205171 was almost 9-fold higher in humans compared with rats. The species differences were still present after P-gp inhibition, although the increase in brain concentrations after P-gp inhibition was somewhat greater in rats than in the other species. Differences in plasma protein binding and metabolism did not explain the species-related differences. The findings are important for interpretation of brain drug delivery when extrapolating preclinical data to humans. Compounds found to be P-gp substrates in rodents are likely to also be substrates in higher species, but sufficient blood-brain barrier permeability may be retained in humans to allow the compound to act at intracerebral targets.

Two C-Methyl Derivatives of [11C]WAY-100635 – Effects of an Amido α-Methyl Group on Metabolism and Brain 5-HT1A Receptor Radioligand Behavior in Monkey*

[carbonyl-11C]N-(2-(1-(4-(2-methoxyphenyl)-piperazinyl)ethyl)-N-pyridinyl)cyclohexanecarboxamide ([carbonyl-11C]WAY-100635) is an effective radioligand for imaging brain 5-HT1A receptors with positron emission tomography (PET). However, this radioligand has some drawbacks for deriving relative regional receptor densities, including rapid metabolism, which acts against accurate definition of an arterial input function for compartmental modeling, and very low nonspecific binding in brain, which detracts from the accuracy of modeling by a simplified reference tissue (cerebellum) approach. Here, in a search for a radioligand that overcomes these limitations, we investigated the effects of introducing a single methyl group at either of the carbon atoms alpha to the amide bond in [11C]WAY-100635. Ligands with a methyl group on the alpha carbon of the cyclohexyl group (SWAY) or the alpha carbon of the C2H4 linker ((R,S)-JWAY) were synthesized and tested for binding affinity and intrinsic activity at 5-HT1A receptors. SWAY was labeled with carbon-11 (t1/2 = 20.4 minutes; beta+ = 99.8%) in its O-methyl group and (R,S)-JWAY in its carbonyl group. Each radioligand was evaluated by PET experiments in cynomolgus monkey. SWAY and (R,S)-JWAY were found to be high-affinity antagonists at 5-HT1A receptors. After injection of [11C]SWAY into monkey, radioactivity uptake in brain reached a maximum of 3% at 4.5 minutes and decreased to 0.7% at 72 minutes. However, over the time span of the experiment, radioactivity concentrations in 5-HT1A receptor-rich brain regions were only fractionally higher than in cerebellum. Radioactivity represented by parent radioligand in plasma was 39% at 45 minutes. After injection of [11C](R,S)-JWAY alone, radioactivity uptake in brain reached a maximum of 4.8% at 2.5 minutes and decreased to 1.2% at 90 minutes. At this time, radioactivity concentration in 5-HT1A receptor-rich brain regions was markedly greater than in cerebellum. In another PET experiment, the monkey was predosed with WAY-100635 before [11C](R,S)-JWAY injection. At 90 minutes after injection, the ratio of radioactivity in 5-HT1A receptor-rich regions to that in cerebellum was reduced to near unity. Radioactivity represented by parent radioligand in plasma was 12% at 45 minutes. [11C](R,S)-JWAY, but not [11C]SWAY, gives a sizeable 5-HT1A receptor-selective PET signal in monkey. The presence of a C-methyl group adjacent to the amide bond in SWAY or (R,S)-JWAY fails to counter metabolism.

Synthesis and in vivo evaluation of 3-[11C]methyl-(3-methoxy-naphthalen)-2-yl-(1-benzyl-piperidin)-4-yl-acetate (SB-235753), as a putative dopamine D4 receptors antagonist for PET

(3-Methoxy-naphthalen)2-yl-(1-benzyl-piperidin)4-yl-acetate (SB-235753) was labelled with 11C (t1/2=20·4 min) as a putative radioligand for the non-invasive assessment of Dopamine D4 receptors in vivo with positron emission tomography (PET). The precursor for the radiosynthesis 3-hydroxynaphthyl-2-[N-benzyl)-piperidyl]-acetate hydrochloride was prepared by a four-step synthesis starting from ethyl-4-pyridyl acetate. The radiolabelling consisted of methylation with [11C]methyltriflate in dimethylformamide in the presence of potassium hydroxide. [11C]SB-235753, was synthesised in 30 min with a radiochemical yield of 10±5% (EOS, non-decay corrected) with 99% radiochemical purity and specific radioactivity of 10±3 Ci/μmol. Biodistribution studies in rats with [11C]SB-235753 showed the uniform distribution of the tracer within different areas of the murine brain. At 30 min after injection 99% of the radioligand in plasma and 100% in cerebellum was metabolised. These findings suggest that [11C]SB-235753 can not be a suitable tracer for dopamine D4 receptor studies with PET. Copyright © 2000 John Wiley & Sons, Ltd.

Synthesis and in vivo evaluation of 3‐[11C]methyl‐(3‐methoxy‐naphthalen)‐2‐yl‐(1‐benzyl‐piperidin)‐4‐yl‐acetate (SB‐235753), as a putative dopamine D4 receptors antagonist for PET

(3-Methoxy-naphthalen)2-yl-(1-benzyl-piperidin)4-yl-acetate (SB-235753) was labelled with 11C (t1/2=20·4 min) as a putative radioligand for the non-invasive assessment of Dopamine D4 receptors in vivo with positron emission tomography (PET). The precursor for the radiosynthesis 3-hydroxynaphthyl-2-[N-benzyl)-piperidyl]-acetate hydrochloride was prepared by a four-step synthesis starting from ethyl-4-pyridyl acetate. The radiolabelling consisted of methylation with [11C]methyltriflate in dimethylformamide in the presence of potassium hydroxide. [11C]SB-235753, was synthesised in 30 min with a radiochemical yield of 10±5% (EOS, non-decay corrected) with 99% radiochemical purity and specific radioactivity of 10±3 Ci/μmol. Biodistribution studies in rats with [11C]SB-235753 showed the uniform distribution of the tracer within different areas of the murine brain. At 30 min after injection 99% of the radioligand in plasma and 100% in cerebellum was metabolised. These findings suggest that [11C]SB-235753 can not be a suitable tracer for dopamine D4 receptor studies with PET. Copyright © 2000 John Wiley & Sons, Ltd.

Quantitation of benzodiazepine receptor binding with PET [ 11C]iomazenil and SPECT [ 123I]iomazenil: preliminary results of a direct comparison in healthy human subjects

Although positron emission tomography (PET) and single photon emission computed tomography (SPECT) are increasingly used for quantitation of neuroreceptor binding, almost no studies to date have involved a direct comparison of the two. One study found a high level of agreement between the two techniques, although there was a systematic 30% increase in measures of benzodiazepine receptor binding in SPECT compared with PET. The purpose of the current study was to directly compare quantitation of benzodiazepine receptor binding in the same human subjects using PET and SPECT with high specific activity [ 11C]iomazenil and [ 123I]iomazenil, respectively. All subjects were administered a single bolus of high specific activity iomazenil labeled with 11C or 123I followed by dynamic PET or SPECT imaging of the brain. Arterial blood samples were obtained for measurement of metabolite-corrected radioligand in plasma. Compartmental modeling was used to fit values for kinetic rate constants of transfer of radioligand between plasma and brain compartments. These values were used for calculation of binding potential (BP= B max/ K d) and product of BP and the fraction of free non-protein-bound parent compound (V3′). Mean values for V3′ in PET and SPECT were as follows: temporal cortex 23±5 and 22±3 ml/g, frontal cortex 23±6 and 22±3 ml/g, occipital cortex 28±3 and 31±5 ml/g, and striatum 4±4 and 7±4 ml/g. These preliminary findings indicate that PET and SPECT provide comparable results in quantitation of neuroreceptor binding in the human brain.

Characterization of bromine-76-labelled 5-bromo-6-nitroquipazine for PET studies of the serotonin transporter

The development of suitable radioligands for brain imaging of the serotonin transporter is of great importance for the study of depression and other affective disorders. The potent and selective serotonin transporter ligand, 5-iodo-6-nitro-2-piperazinylquinoline, has been labelled with iodine-123 and used as a radioligand for single photon emission computerized tomography. To evaluate the potential of the bromine-76-labelled analogue, 5-bromo-6-nitroquipazine, as a radioligand for positron emission tomography (PET), its brain distribution and binding characteristics were examined in rats. In vivo brain distribution and ex vivo autoradiography demonstrated that [ 76Br]5-bromo-6-nitroquipazine enters the brain rapidly. The regional brain distribution of [ 76Br]5-bromo-6-nitroquipazine was consistent with the known distribution of serotonin transporters in the midbrain, pons, thalamus, striatum, and neocortex. Specific binding was inhibited by the selective serotonin reuptake inhibitor citalopram. The peripheral metabolism in plasma was rapid, but more than 90% of the radioactivity in brain represented unchanged radioligand 2 h postinjection (p.i.). A preliminary PET study was also performed in a baboon. Following the intravenous injection of [ 76Br]5-bromo-6-nitroquipazine in a baboon, there was a conspicuous accumulation of radioactivity in thalamus, striatum, and pons. The radioactivity in these brain regions was 1.5 times higher than in the cerebellum at 3 h and 2.5–4 times higher at 24 h. A rapid metabolism of the radioligand in plasma was observed (38% unchanged after 5 min). The results indicate that [ 76Br]5-bromo-6-nitroquipazine has potential for PET imaging of the serotonin transporter.

On the biological treatment of autistic disorder

The development of suitable radioligands for brain imaging of the serotonin transporter is of great importance for the study of depression and other affective disorders. The potent and selective serotonin transporter ligand, 5-iodo-6-nitro-2-piperazinylquinoline, has been labelled with iodine-123 and used as a radioligand for single photon emission computerized tomography. To evaluate the potential of the bromine-76-labelled analogue, 5-bromo-6-nitroquipazine, as a radioligand for positron emission tomography (PET), its brain distribution and binding characteristics were examined in rats. In vivo brain distribution and ex vivo autoradiography demonstrated that [76Br]5-bromo-6-nitroquipazine enters the brain rapidly. The regional brain distribution of [76Br]5-bromo-6-nitroquipazine was consistent with the known distribution of serotonin transporters in the midbrain, pons, thalamus, striatum, and neocortex. Specific binding was inhibited by the selective serotonin reuptake inhibitor citalopram. The peripheral metabolism in plasma was rapid, but more than 90% of the radioactivity in brain represented unchanged radioligand 2 h postinjection (p.i.). A preliminary PET study was also performed in a baboon. Following the intravenous injection of [76Br]5-bromo-6-nitroquipazine in a baboon, there was a conspicuous accumulation of radioactivity in thalamus, striatum, and pons. The radioactivity in these brain regions was 1.5 times higher than in the cerebellum at 3 h and 2.5–4 times higher at 24 h. A rapid metabolism of the radioligand in plasma was observed (38% unchanged after 5 min). The results indicate that [76Br]5-bromo-6-nitroquipazine has potential for PET imaging of the serotonin transporter.

Loss of brain 5-HT2 receptors in Alzheimer's disease. In vivo assessment with positron emission tomography and [18F]setoperone.

Using [18F]setoperone and positron emission tomography (PET), alterations in serotonergic 5-HT2 receptor binding were studied in cerebral cortex of nine unmedicated patients with probable Alzheimer's disease and 37 healthy controls. The kinetics of unchanged radioligand in plasma and 18F-radioactivity in blood and brain were obtained for 90 min following tracer injection. The specific binding of [18F]setoperone to 5-HT2 receptors in the cerebral cortex was quantitated by subtraction using cerebellum as reference. In controls, a significant reduction in specific binding was associated with age and similar linear regression slopes were obtained in all the cortical regions studied. No significant difference was observed between patients with Alzheimer's disease and age-matched controls in the injected mass of setoperone, percentage of unmetabolized [18F]setoperone in plasma, 18F-radioactivity in blood fractions and cerebellar 18F-radioactivity concentration, indicating similar non-specific brain kinetics and metabolism of the radioligand. In contrast, there was a significant reduction in specific [18F]setoperone binding in the cerebral cortex in patients with Alzheimer's disease relative to control values (temporal, 69%; frontal, 69%; parietal, 55%; temporo-parietal, 54%; occipital cortex, 35%). The results demonstrate that the loss in 5-HT2 receptor binding in the cerebral cortex of patients with Alzheimer's disease, long documented by post-mortem studies, can now be assessed in vivo using PET.