On the quantification of [18F]MPPF binding to 5-HT1A receptors in the human brain.

Previous studies have shown that 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[(18)F]fluorobenzamido]ethylpiperazine ([(18)F]MPPF) binds with high selectivity to serotonin (5-HT(1A)) receptors in man. However, in these studies, the calculation of the binding potential (BP, which equals receptor density divided by equilibrium dissociation constant) used a metabolite-corrected arterial input. The aim of this study was to determine whether metabolite correction and arterial sampling are essential for the assessment of BP. METHODS: Five analytic methods using full datasets obtained from 6 healthy volunteers were compared. In addition, the clinical applicability of these methods was appraised. Three methods were based on Logan analysis of the dynamic PET data using metabolite-corrected and uncorrected arterial plasma input and cerebellar input. The other 2 methods consisted of a simplified reference tissue model and standard compartmental modeling. RESULTS: A high correlation was found between BP calculated with Logan analysis using the metabolite-corrected plasma input (used as the reference method for this study) and Logan analysis using either the uncorrected arterial plasma input (r(2) = 0.95, slope = 0.85) or cerebellar input (r(2) = 0.98, slope = 0.91). A high correlation was also found between our reference method and the simplified reference tissue model (r(2) = 0.94, slope = 0.92). In contrast, a poor correlation was observed between our reference method and the standard compartmental model (r(2) = 0.45, slope = 1.59). CONCLUSION: These results indicate that neither metabolite analysis nor arterial sampling is necessary for clinical evaluation of BP in the human brain with [(18)F]MPPF. Both the Logan analysis method with cerebellar input and the simplified reference tissue method can be applied clinically.     

PET quantification of 5-HT2A receptors in the human brain: a constant infusion paradigm with [18F]altanserin.

[18F]altanserin has been used to label serotonin 5-HT2A receptors, which are believed to be important in the pathophysiology of schizophrenia and depression. The purpose of this study was to test the feasibility of a constant infusion paradigm for equilibrium modeling of [18F]altanserin with PET. Kinetic modeling with [18F]altanserin may be hampered by the presence of lipophilic radiometabolites observed in plasma after intravenous administration. METHODS: Eight healthy volunteers were injected with [18F]altanserin as a bolus (208+/-9 MBq [5.62+/-0.25 mCi]) plus constant infusion (65+/-3 MBq/h [1.76+/-0.08 mCi/h]) ranging from 555 to 626 min (615+/-24 min) after injection. PET acquisitions (10-20 min) and venous blood sampling were performed every 30-60 min throughout the infusion period. RESULTS: Linear regression analysis revealed that time-activity curves for both brain activity and plasma [18F]altanserin and metabolite concentrations stabilized after about 6 h. This permitted equilibrium modeling and estimation of V3' (ratio of specific uptake [cortical-cerebellar] to total plasma parent concentration after 6 h). Values of V3' ranged from 1.57+/-0.38 for anterior cingulate cortex to 1.02+/-0.39 for frontal cortex. The binding potential V3 (ratio of specific uptake to free plasma parent concentration after 6 h, using group mean f1) was also calculated and ranged from 169+/-41 for anterior cingulate cortex to 110+/-42 for frontal cortex. From 6 h onward, the rate of change for V3' and V3 was only 1.11+/-1.69 %/h. CONCLUSION: These results demonstrate the feasibility of equilibrium imaging with [18F]altanserin over more than 5 radioactive half-lives and suggest a method to overcome difficulties associated with lipophilic radiolabeled metabolites. The stability in V3 and V3' once equilibrium is achieved suggests that a single PET acquisition obtained at 6 h may provide a reasonable measure of 5-HT2A receptor density.     

Improved delineation of human dopamine receptors using [18F]-N-methylspiroperidol and PET

The brain uptake of [18F]-N-methylspiroperidol, a butyrophenone neuroleptic with high selectivity for the dopamine receptor, has been measured in three normal human volunteers using positron emission tomography for times up to 12 hr postinjection. These studies demonstrated two unique findings concerning the in vivo distribution of this neuroleptic: (a) it is tightly bound to dopamine D-2 receptors in the caudate-putamen brain regions, and (b) these regions are the only large brain structures which exhibit appreciable long-term retention. In addition, radioactivity clears rapidly from plasma, and the percentage of unchanged [18F]-N-methylspiroperidol in plasma declines rapidly. These results suggest that this compound binds irreversibly to dopamine D-2 receptors, and that there are few if any dopamine D-2 receptors in the human frontal cortex. These studies emphasize not only the importance of characterizing neurotransmitter receptors in living human brain using a ligand labeled with a positron emitting nuclide of sufficiently long half-life to allow monitoring of brain radioactivity distribution for several hours after the injection of radioligand, but also of accurately determining the amount of unchanged tracer in plasma for tracer kinetic modeling.     

Preliminary in vivo and ex vivo evaluation of the 5-HT2A imaging probe [18F]MH.MZ

IntroductionThe 5-HT_2A receptor is one of the most interesting targets within the serotonergic system because it is involved in a number of important physiological processes and diseases.Methods[¹⁸F]MH.MZ, a 5-HT_2A antagonistic receptor ligand, is labeled by ¹⁸F-fluoroalkylation of the corresponding desmethyl analogue MDL 105725 with 2-[¹⁸F]fluoroethyltosylate ([¹⁸F]FETos). In vitro binding experiments were performed to test selectivity toward a broad spectrum of neuroreceptors by radioligand binding assays. Moreover, first micro-positron emission tomography (μPET) experiments, ex vivo organ biodistribution, blood cell and protein binding and brain metabolism studies of [¹⁸F]MH.MZ were carried out in rats.Results[¹⁸F]MH.MZ showed a K_i of 3 nM toward the 5-HT_2A receptor and no appreciable affinity for a variety of receptors and transporters. Ex vivo biodistribution as well as μPET showed highest brain uptake at ～5 min p.i. and steady state after ～30 min p.i. While [¹⁸F]MH.MZ undergoes extensive first-pass metabolism which significantly reduces its bioavailability, it is insignificantly metabolized within the brain. The binding potential in the rat frontal cortex is 1.45, whereas the cortex to cerebellum ratio was determined to be 2.7 after ～30 min.ConclusionResults from μPET measurements of [¹⁸F]MH.MZ are in no way inferior to data known for [¹¹C]MDL 100907 at least in rats. [¹⁸F]MH.MZ appears to be a highly potent and selective serotonergic PET ligand in small animals.     

In vivo PET quantification of the dopamine transporter in rat brain with [18F]LBT-999

IntroductionWe examined whether [¹⁸F]LBT-999 ((E)-N-(4-fluorobut-2-enyl)2β-carbomethoxy-3β-(4’-tolyl)nortropane) is an efficient positron emission tomography (PET) tracer for the quantification of the dopamine transporter (DAT) in the healthy rat brain.MethodsPET studies were performed using several experimental designs, i.e. test-retest, co-injection with different doses of unlabelled LBT, displacement with GBR12909 and pre-injection of amphetamine.ResultsThe uptake of [¹⁸F]LBT-999 confirmed its specific binding to the DAT. The non-displaceable uptake (BP_ND) in the striatum, between 5.37 and 4.39, was highly reproducible and reliable, and was decreased by 90% by acute injection of GBR12909. In the substantia nigra/ventral tegmental area (SN/VTA), the variability was higher and the reliability was lower. Pre-injection of amphetamine induced decrease of [¹⁸F]LBT-999 BP_ND of 50% in the striatum.Conclusions[¹⁸F]LBT-999 allows the quantification of the DAT in living rat brain with high reproducibility, sensitivity and specificity. It could be used to quantify the DAT in rodent models, thereby allowing to study neurodegenerative and neuropsychiatric diseases.     

PET imaging of brain 5-HT1A receptors in rat in vivo with 18F-FCWAY and improvement by successful inhibition of radioligand defluorination with miconazole.

18F-FCWAY (18F-trans-4-fluoro-N-(2-[4-(2-methoxyphenyl) piperazin-1-yl)ethyl]-N-(2-pyridyl)cyclohexanecarboxamide) is useful in clinical research with PET for measuring serotonin 1A (5-HT1A) receptor densities in brain regions of human subjects but has significant bone uptake of radioactivity due to defluorination. The uptake of radioactivity in skull compromises the accuracy of measurements of 5-HT1A receptor densities in adjacent areas of brain because of spillover of radioactivity through the partial-volume effect. Our aim was to demonstrate with a rat model that defluorination of 18F-FCWAY may be inhibited in vivo to improve its applicability to measuring brain regional 5-HT1A receptor densities. METHODS: PET of rat head after administration of 18F-FCWAY was used to confirm that the distribution of radioactivity measured in brain is dominated by binding to 5-HT1A receptors and to reveal the extent of defluorination of 18F-FCWAY in vivo as represented by radioactivity (18F-fluoride ion) uptake in skull. Cimetidine, diclofenac, and miconazole, known inhibitors of CYP450 2EI, were tested for the ability to inhibit defluorination of 18F-FCWAY in rat liver microsomes in vitro. The effects of miconazole treatment of rats on skull radioactivity uptake and, in turn, its spillover on brain 5-HT1A receptor imaging were assessed by PET with venous blood analysis. RESULTS: PET confirmed the potential of 18F-FCWAY to act as a radioligand for 5-HT1A receptors in rat brain and also revealed extensive defluorination. In rat liver microsomes in vitro, defluorination of 18F-FCWAY was almost completely inhibited by miconazole and, to a less extent, by diclofenac. In PET experiments, treatment of rats with miconazole nitrate (60 mg/kg intravenously) over the 45-min period before administration of 18F-FCWAY almost obliterated defluorination and bone uptake of radioactivity. Also, brain radioactivity almost doubled while the ratio of radioactivity in receptor-rich ventral hippocampus to that in receptor-poor cerebellum almost tripled to 14. The plasma half-life of radioligand was also extended by miconazole treatment. CONCLUSION: Miconazole treatment, by eliminating defluorination of 18F-FCWAY, results in effective imaging of brain 5-HT1A receptors in rat. 18F-FCWAY PET in miconazole-treated rats can serve as an effective platform for investigating 5-HT1A receptors in rodent models of neuropsychiatric conditions or drug action.     

Characterization of radioactive metabolites of 5-HT2A receptor PET ligand [18F]altanserin in human and rodent

This study was performed to identify and characterize the radiometabolites of the serotonin 5-HT2A receptor ligand [18F]altanserin in supporting quantification of the target receptors by positron emission tomography. In analogy to its analog ketanserin, we postulated 4-(4-fluorobenzoyl)piperidine (FBP) and altanserinol for the previously observed two polar radiometabolites, corresponding to dealkylation at the piperidine nitrogen and reduction at the ketone, respectively. To test this hypothesis and characterize the in vivo and in vitro behavior of the radiometabolites, we synthesized nonradioactive authentic compounds altanserinol, 1-(4-fluorophenyl)-1-(piperidin-4-yl)methanol (FBPOH), and isolated nonradioactive FBP metabolite from monkey plasma. [18F]Altanserinol was obtained by NaBH4 reduction of [18F]altanserin, followed by acid hydrolysis. Identification of radiometabolites was carried out by high performance liquid chromatography and thin layer chromatography comparison of the radioactive plasma after injection of tracers with five authentic compounds. Human studies revealed that at least four radiometabolites, one identified as [18F]altanserinol, resulted from reduction of the ketone functionality. The N-dealkylation product [18F]FBP was not detectable; however, a radiometabolite of FBP was present in plasma after administration of [18F]altanserin. Monkey studies showed nonradioactive FBP was converted rapidly to a less polar metabolite. In rat, altanserin and altanserinol were converted to each other in vivo, and all the radiometabolites likely penetrated the blood-brain barrier and entered the brain. Displacement binding of altanserin to cloned serotonin 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors showed Ki values of 0.3, 6.0, 1,756, and 15 nM; the binding of FBP and altanserinol to these four 5-HT subtypes was negligible. We conclude from these studies that the radiometabolites of [18F]altanserin from N-dealkylation and ketone reduction should not interfere with specific receptor quantification in an equilibrium paradigm.     

[18F]F15599, a novel 5-HT1A receptor agonist, as a radioligand for PET neuroimaging

Purpose  

The serotonin-1A (5-HT_1A) receptor is implicated in the pathophysiology of major neuropsychiatric disorders. Thus, the functional imaging of 5-HT_1A receptors by positron emission tomography (PET) may contribute to the understanding of its role in those pathologies and their therapeutics. These receptors exist in high- and low-affinity states and it is proposed that agonists bind preferentially to the high-affinity state of the receptor and therefore could provide a measure of the functional 5-HT_1A receptors. Since all clinical PET 5-HT_1A radiopharmaceuticals are antagonists, it is of great interest to develop a ¹⁸F labelled agonist.     

Synthesis,radiofluorination and first evaluation of [18F]fluorophenylsulfonyl- and [18F]fluorophenylsulfinyl-piperidines as serotonin 5-HT2A receptor antagonists for PET

In psychiatric disorders, 5-HT_2A receptors play an important role. In order to study these receptors in vivo by positron emission tomography (PET), there is an increasing interest for subtype selective and high affinity radioligands. Up to now, no optimal radiotracer is available. Thus, 1-(2,4-difluorophenethyl)-4-(4-fluorophenylsulfonyl)piperidine (9), possessing high affinity and sufficient subtype selectivity for 5-HT_2A receptors, and 1-(2,4-difluorophenethyl)-4-(4-fluorophenylsulfinyl)piperidine (15) have been ¹⁸F-labelled by a nucleophilic one-step reaction. Both radiotracers could be prepared and isolated within 45 min, [¹⁸F]9 in a radiochemical yield (RCY) of 34.5±8% and [¹⁸F]15 of 9.5±2.5%. The K_i values of 9 and 15 at 5-HT_2A receptors towards [³H]ketanserin were determined to be 1.9±0.6 and 198±8 nM, respectively. Autoradiography with [¹⁸F]9 and [¹⁸F]15 on rat brain sections showed a very high nonspecific binding of >80% for [¹⁸F]9 and 30% to 40% nonspecific binding for [¹⁸F]15; however, it is still too high in order to compensate for its lower affinity. Even though the affinity of 9 is more promising compared with 15, the high nonspecific binding of both radiofluorinated tracers in rat brain does not recommend those as an in vivo PET imaging agent for serotonin 5-HT_2A receptors in humans.     

(18)F]p-MPPF: aA radiolabeled antagonist for the study of 5-HT(1A) receptors with PET

This paper summarizes the present status of the researches conducted with [(18)F]4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p-fluorobenzamido ]ethyl]-piperazine known as [(18)F]p-MPPF, a new 5-HT(1A) antagonist for the study of the serotonergic neurotransmission with positron emission tomography (PET). This includes chemistry, radiochemistry, animal data (rats, cats, and monkeys) with autoradiography and PET, human data with PET, toxicity, and metabolism.     

Equilibrium modeling of 5-HT(2A) receptors with [18F]deuteroaltanserin and PET: feasibility of a constant infusion paradigm

ABSTRACT. [¹⁸F]Altanserin has emerged as a promising positron emission tomography (PET) ligand for serotonin-2A (5-HT_2A) receptors. The deuterium substitution of both of the 2′-hydrogens of altanserin ([¹⁸F]deuteroaltanserin) yields a metabolically more stable radiotracer with higher ratios of parent tracer to radiometabolites and increased specific brain uptake than [¹⁸F]altanserin. The slower metabolism of the deuterated analog might preclude the possibility of achieving stable plasma and brain activities with a bolus plus constant infusion within a reasonable time frame for an ¹⁸F-labeled tracer (T_1/2 110 min). Thus, the purpose of this study was to test the feasibility in human subjects of a constant infusion paradigm for equilibrium modeling of [¹⁸F]deuteroaltanserin with PET. Seven healthy male subjects were injected with [¹⁸F]deuteroaltanserin as a bolus plus constant infusion lasting 10 h postinjection. PET acquisitions and venous blood sampling were performed throughout the infusion period. Linear regression analysis revealed that time-activity curves for both specific brain uptake and plasma [¹⁸F]deuteroaltanserin concentration stabilized after about 5 h. This permitted equilibrium modeling and estimation of V^′₃ (ratio of specific uptake to total plasma parent concentration) and the binding potential V₃ (ratio of specific uptake to free plasma parent concentration). Cortical/cerebellar ratios were increased by 26% relative to those we previously observed with [¹⁸F]altanserin using similar methodology in a somewhat older subject sample. These results demonstrate feasibility of equilibrium imaging with [¹⁸F]deuteroaltanserin and suggest that it may be superior to [¹⁸F]altanserin as a PET radioligand.     

Synthesis and tumour-localizing properties of [18F]-5-fluorocytosine-arabinoside and [18F]-5-fluorocyclocytidine

[¹⁸F]-5-fluorocytosine-arabinoside (2) and [¹⁸F]-5-fluorocyclocytidine (4) were prepared by reaction of [¹⁸F]-acetylhypofluorite with cytosine-arabinoside (1) or cyclocytidine (3) in acetic acid and were isolated in an overall radiochemical yield of 20% and 9%, respectively. The biodistribution of both radiopharmaceuticals was determined in melanoma bearing Syrian golden hamsters. It was found that 2 is a good tumour-localizing agent for pigmented and non-pigmented Greene melanoma.     

Synthesis and tumour-localizing properties of [18F]-5-fluorocytosine-arabinoside and [18F]-5-fluorocyclocytidine

[18F]-5-fluorocytosine-arabinoside (2) and [18F]-5-fluorocyclocytidine (4) were prepared by reaction of [18F]-acetylhypofluorite with cytosine-arabinoside (1) or cyclocytidine (3) in acetic acid and were isolated in an overall radiochemical yield of 20% and 9%, respectively. The biodistribution of both radiopharmaceuticals was determined in melanoma bearing Syrian golden hamsters. It was found that 2 is a good tumour-localizing agent for pigmented and non-pigmented Greene melanoma.     

Quantification of 5-HT1A receptors in human brain using p-MPPF kinetic modelling and PET

Serotonin-1A (5-HT(1A)) receptors are implicated in neurochemical mechanisms underlying anxiety and depression and their treatment. Animal studies have suggested that 4-(2'-methoxyphenyl)-1-[2'-[ N-(2"-pyridinyl)- p-[(18)F]fluorobenzamido] ethyl] piperazine ( p-MPPF) may be a suitable positron emission tomography (PET) tracer of 5-HT(1A) receptors. To test p-MPPF in humans, we performed 60-min dynamic PET scans in 13 healthy volunteers after single bolus injection. Metabolite quantification revealed a fast decrease in tracer plasma concentration, such that at 5 min post injection about 25% of the total radioactivity in plasma corresponded to p-MPPF. Radioactivity concentration was highest in hippocampus, intermediate in neocortex and lowest in basal ganglia and cerebellum. The interactions between p-MPPF and 5-HT(1A) receptors were described using linear compartmental models with plasma input and reference tissue approaches. The two quantification methods provided similar results which are in agreement with previous reports on 5-HT(1A) receptor brain distribution. In conclusion, our results show that p-MPPF is a suitable PET radioligand for 5-HT(1A) receptor human studies.     

Imaging central nicotinic acetylcholine receptors in baboons with [18F]fluoro-A-85380.

Central nicotinic acetylcholine receptors (nAChRs) have been implicated in learning-memory processes. Postmortem brain tissue of patients who suffered senile dementia or Parkinson's disease shows low density of nAChRs. In this study, we used PET to evaluate the distribution and kinetics of the fluoro derivative of the high-affinity and alpha4beta2-subtype-selective, nicotinic ligand 3-[2(S)-2-azetidinylmethoxy]pyridine (A-85380) in baboons. METHODS: After intravenous injection of 37 MBq (1 mCi, 1-1.5 nmol) [18F]fluoro-A-85380 into isoflurane-anesthetized baboons, dynamic PET data were acquired for 180 min. Time-activity curves were generated from regions of interest. Displacement experiments (80 min after injection of the radiotracer) were performed using cytisine (1 mg/kg subcutaneously) and unlabeled fluoro-A-85380 (0.1 and 0.3 mg/kg intravenously). Toxicological studies were performed in mice. RESULTS: Brain radioactivity reached a plateau within 40-50 min of injection of the tracer. In the thalamic area, radioactivity remained constant for 180 min, while clearance from the cerebellum was slow (t1/2 = 145-190 min). Cytisine and unlabeled fluoro-A-85380 reduced brain radioactivity at 180 min by 50%-60%, 30%-35% and 20%-35% of control values in the thalamus, cerebellum and frontal cortex, respectively. A slight, transient increase (20 mm Hg) in blood pressure was observed with the highest displacing dose of unlabeled fluoro-A-85380. Lethal dose in mice was found to be 2.2 mg/kg intravenously. CONCLUSION: These results demonstrate the feasibility and the safety of imaging nAChRs in vivo using labeled or unlabeled fluoro-A-85380.     

High-resolution imaging of brain 5-HT1B receptors in the rhesus monkey using [11C]P943

The serotonin 5-HT_1B receptors regulate the release of serotonin and are involved in various disease states, including depression and schizophrenia. The goal of the study was to evaluate a high affinity and high selectivity antagonist, [¹¹C]P943, as a positron emission tomography (PET) tracer for imaging the 5-HT_1B receptor. [¹¹C]P943 was synthesized via N-methylation of the precursor with [¹¹C]methyl iodide or [¹¹C]methyl triflate using automated modules. The average radiochemical yield was approx. 10% with radiochemical purity of >99% and specific activity of 8.8±3.6 mCi/nmol at the end-of-synthesis (n=37). PET imaging was performed in non-human primates with a high-resolution research tomograph scanner with a bolus/infusion paradigm. Binding potential (BP_ND) was calculated using the equilibrium ratios of regions to cerebellum. The tracer uptake was highest in the globus pallidus and occipital cortex, moderate in basal ganglia and thalamus, and lowest in the cerebellum, which is consistent with the known brain distribution of 5-HT_1B receptors. Infusion of tracer at different specific activities (by adding various amount of unlabeled P943) reduced BP_ND values in a dose-dependent manner, demonstrating the saturability of the tracer binding. Blocking studies with GR127935 (2 mg/kg iv), a selective 5-HT_1B/5-HT_1D antagonist, resulted in reduction of BP_ND values by 42-95% across regions; for an example, in occipital region from 0.71 to 0.03, indicating a complete blockade. These results demonstrate the saturability and specificity of [¹¹C]P943 for 5-HT_1B receptors, suggesting its suitability as a PET radiotracer for in vivo evaluations of the 5-HT_1B receptor system in humans.     

Biodistribution of [18F] SR144385 and [18F] SR147963: selective radioligands for positron emission tomographic studies of brain cannabinoid receptors

ABSTRACT. [¹⁸F] SR144385 and [¹⁸F] SR147963 were synthesized in a multistep reaction in which fluorine-18 was introduced by nucleophilic halogen displacement on a bromo precursor. The fluorine-18-labeled intermediate was deprotected and coupled with the appropriate alkyl amine to give the final products. Both radioligands had appropriate regional brain distribution for cannabinoid receptors with a target to nontarget ratio of 1.7 for [¹⁸F] SR147963 and 2.5 for [¹⁸F] SR144385 at 60 and 90 min postinjection, respectively. The uptake of both tracers was blocked with a 1 mg/kg dose of SR141716A.     

Regioselective radiofluorodestannylation with [18F]F2 and [18F]CH3COOF: A high yield synthesis of 6-[18F]fluoro-l-dopa

A protected 6-trimethylstannyl dopa derivative 6 has been synthesized for the first time as a precursor for the preparation of 6-[¹⁸F]fluoro-l-dopa. The tin derivative 6 readily reacted with electrophilic radiofluorinating agents such as [¹⁸F]F₂ and [¹⁸F]AcOF. The [¹⁸F]fluoro intermediate 7 was easily hydrolyzed with HBr and the product 6-[¹⁸F]fluoro-l-dopa was isolated after HPLC purification in a maximum radiochemical yield of 25%, ready for human use. The various intermediates, the stannyl precursor 6 and the final product (after ¹⁸F decay) were all fully characterized by ¹H, ¹³C, ¹⁹F and ¹¹⁹Sn NMR as well as high resolution mass spectroscopy.     

Kinetic analysis of the cannabinoid-1 receptor PET tracer [18F]MK-9470 in human brain

Purpose

Quantitative imaging of the type 1 cannabinoid receptor (CB1R) opens perspectives for many neurological and psychiatric disorders. We characterized the kinetics and reproducibility of the CB1R tracer [¹⁸F]MK-9470 in human brain.

Methods

[¹⁸F]MK-9470 data were analysed using reversible models and the distribution volume V _T and V _ND k ₃ (V _ND k ₃ = K ₁ k ₂) were estimated. Tracer binding was also evaluated using irreversible kinetics and the irreversible uptake constant K _i and fractional uptake rate (FUR) were estimated. The effect of blood flow on these parameters was evaluated. Additionally, the possibility of determining the tracer plasma kinetics using a reduced number of blood samples was also examined.

Results

A reversible two-tissue compartment model using a global k ₄ value was necessary to describe brain kinetics. Both V _T and V _ND k ₃ were estimated satisfactorily and their test–retest variability was between 10% and 30%. Irreversible methods adequately described brain kinetics and FUR values were equivalent to K _i. The linear relationship between K _i and V _ND k ₃ demonstrated that K _i or FUR and thus the simple measure of tracer brain uptake provide CB1R availability information. The test–retest variability of K _i and FUR was <10% and estimates were independent of blood flow. Brain uptake can be used as a receptor availability index, albeit at the expense of potential bias due to between-subject differences in tracer plasma kinetics.

Conclusion

[¹⁸F]MK-9470 specific binding can be accurately determined using FUR values requiring a short scan 90 to 120 min after tracer administration. Our results suggest that [¹⁸F]MK-9470 plasma kinetics can be assessed using a few venous samples.