123I-5-IA-85380 SPECT imaging of nicotinic acetylcholine receptor availability in nonsmokers: effects of sex and menstrual phase.

The study of the effects of sex and hormones on brain chemistry and neurotransmission is of increasing importance as evidence emerges of sex differences in behavioral symptoms and treatment response in neuropsychiatric disorders. The nicotinic acetylcholine receptor (nAChR) system has been implicated in a variety of psychiatric disorders, including tobacco smoking, for which there is strong evidence supporting sex differences in behaviors and response to smoking cessation treatments. We examined the availability of nAChR containing the beta(2) subunit in healthy men and women and the influence of menstrual phase among women. METHODS: Ten men and 19 women nonsmokers underwent one (123)I-5-IA-85380 ((123)I-5-IA) SPECT scan and one MRI scan. A subset of 9 women, aged 18-39 y, underwent a second (123)I-5-IA scan. These 9 women were scanned during the early follicular (days 4-7 in 8 subjects and day 11 in 1 subject) and mid-luteal (days 19-25) phases of their menstrual cycle. Hormone levels were measured in all women to confirm the phase of the cycle. RESULTS: Regional brain activity (kBq/cm(3)) was higher (39%-54%) in women than in men nonsmokers. When regional brain activity was normalized to total plasma parent to correct for individual differences in radiotracer metabolism (V(T)'), differences of 10%-16% were observed, with women greater than men. In contrast, when regional brain activity was normalized to free plasma parent (V(T)), there was less than a 4% difference by sex in regional brain beta(2)-nAChR availability. These sex differences in kBq/cm(3) and V(T)' resulted from significantly higher levels of total plasma parent, free fraction (f(1)), and free plasma parent in women than in men nonsmokers. No differences in plasma measures or brain beta(2)-nAChR availability were observed across the menstrual cycle for any outcome measure. CONCLUSION: Overall, these findings demonstrate no significant difference in brain beta(2)-nAChR availability between men and women nonsmokers or across the menstrual cycle. Importantly, these findings demonstrate sex differences in radiotracer metabolism and plasma protein binding and highlight the critical need to measure plasma radiotracer levels and f(1) in studies that include both sexes.     

Quantification of human nicotinic acetylcholine receptors with 123I-5IA SPECT.

Neuronal nicotinic acetylcholine receptors (nAChRs) are widely distributed in the human brain, especially the alpha4beta2 subtype of nAChR. The cholinergic systems have roles in various neurophysiologic functions, such as learning, memory, and cognition, whereas normal aging and neurodegenerative diseases have been associated with changes in nAChRs. Recently, 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5IA) has been synthesized as a radioligand for imaging nAChRs with SPECT. 123I-5IA shows higher affinity toward the nAChR alpha4beta2 subtype, enhanced receptor subtype selectivity, good safety, and low nonspecific binding. METHODS: In this study, a SPECT quantitative study of human nAChRs binding with 123I-5IA was conducted in healthy volunteers. An arterial input function was obtained for each subject and a 2-compartment model was used to determine the kinetic parameters of 123I-5IA using data from a 6-h scan. The distribution volume (VT (mL/mL), which is related to the number of unoccupied binding sites in the brain, was calculated and values were compared with results of a graphical analysis (Logan plot, VLG). RESULTS: Analysis of the unmetabolized compound showed a high parent fraction of 123I-5IA in plasma. The results from the 2-compartment model analysis showed high VT values for the thalamus; moderate values for the brain stem, cerebellum, and basal ganglia; and low values for the cortical regions. Good agreement was observed between VT values and results of autoradiographic experiments done in vitro for nAChR density in human brain. A high correlation index was observed between distribution volumes from model and graphical analyses. CONCLUSION: Our results indicated that 123I-5IA SPECT is suitable for the quantification of nAChRs in human brain.     

Quantification of nicotinic acetylcholine receptors in human brain using [123I]5-I-A-85380 SPET

The purpose of this study was to assess the utility of a new single-photon emission tomography ligand, [¹²³I]5-iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380), to measure regional nAChR binding in human brain. Six healthy nonsmoker subjects (two men and four women, age 33±15 years) participated in both a bolus (dose: 317±42 MBq) and a bolus plus constant infusion (dose of bolus: 98±32 MBq, B/I=6.7±2.6 h, total dose: 331±55 MBq) study. The study duration was 5–8 h and 14 h in the former and the latter, respectively. Nonlinear least-squares compartmental analysis was applied to bolus studies to calculate total (V_T) and specific (V_S) distribution volumes. A two-tissue compartment model was applied to identify V_S. V_T was also calculated in B/I studies. In bolus studies, V_T was well identified by both one- and two-tissue compartment models, with a coefficient of variation of less than 5% in most regions. The two-compartment model gave V_T values of 51, 22, 27, 32, 20, 19, 20, and 17 ml cm^–3 in thalamus, cerebellum, putamen, pons, and frontal, parietal, temporal, and occipital cortices, respectively. The two-compartment model did not identify V_S well. B/I studies provided poor accuracy of V_T measurement, possibly due to deviations from equilibrium conditions. These results demonstrate the feasibility of quantifying high-affinity type nAChRs using [¹²³I]5-I-A-85380 in humans and support the use of V_T measured by bolus studies.     

Measurement of alpha4beta2 nicotinic acetylcholine receptors with [123I]5-I-A-85380 SPECT.

Nicotinic acetylcholine receptors (nAChRs) play an important role in tobacco dependence and a potential therapeutic role in neuropsychiatric disorders such as Alzheimer's disease. [123I]5-iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380) is a new SPECT tracer that labels alpha4beta2 nAChRs. The purpose of this study was to assess the usefulness of this tracer to measure regional nAChR binding in baboon brain using both a bolus/kinetic paradigm and also a bolus plus constant infusion/equilibrium paradigm. METHODS: A pair of bolus/kinetic and bolus plus constant infusion/equilibrium studies was performed in each of 3 isoflurane-anesthetized baboons. Bolus studies were performed by intravenous injection of 191-226 MBq [123I]5-I-A-85380 and image acquisition for 289-367 min. The data were analyzed with 1- and 2-tissue compartment models. Bolus plus constant infusion/equilibrium studies were performed by a bolus injection (74-132 MBq) followed by a 468- to 495-min infusion with a bolus/infusion ratio (B/I) of 4.8-5.0 h. The distribution volumes in the thalamus were measured in these 2 paradigms. To study whether the cerebellum was appropriate as a receptor-poor region, displacement studies were done in 2 baboons using the B/I paradigm with subcutaneous injection of (-)-cytisine (0.8 and 1.0 mg/kg). RESULTS: The kinetics of this tracer was best described by the 1-tissue compartment model. The 2-compartment model showed poor identifiability of rate constants. The total (specific plus nondisplaceable compartments) distribution volumes (V(T)') agreed between bolus and B/I paradigms (average percentage difference in V(T)', 16.8%). (-)-Cytisine (0.8 and 1.0 mg/kg) displaced 70% and 72% of the radioactivity in the thalamus and 36% and 55% in the cerebellum, respectively, indicating that the latter was not appropriate as a receptor-poor region. CONCLUSION: These results show the feasibility of quantifying alpha4beta2 nAChRs using [123I]5-I-A-85380 and support the use of V(T)' as an appropriate outcome measure.     

Chemical fate of the nicotinic acetylcholinergic radiotracer [123I]5-IA-85380 in baboon brain and plasma

The fate of the nicotinic acetylcholinergic receptor radiotracer [123I]5-IA-85380 ([123I]5-IA) was studied in baboon by analyzing the chemical composition of brain tissue and plasma after intravenous administration of the tracer. Acetonitrile denaturation and high-performance liquid chromatography (HPLC) analysis showed predominantly unchanged (91-98%) parent tracer in all brain tissues examined, compared to significant metabolism (23% parent) in the plasma at 90 min postinjection, and control tissue recovery of 95-98%. [123I]5-IA was distributed to the thalamus with a standardized uptake value of 9.2 (0.04% dose/g) or a concentration 5.8 times higher than that of the cerebellum. The HPLC behavior of a synthesized sample of one hypothesized metabolite, 5-iodo-3-pyridinol (5-IP), was consistent with plasma radiometabolite fraction. Since only parent radiotracer compound was found in brain tissue, these results add confidence that information derived from single photon emission computed tomography images of 123I activity in the brain after [123I]5-IA administration can be interpreted as distribution of an intact radiotracer.     

Synthesis of an I-123 analog of A-85380 and preliminary SPECT imaging of nicotinic receptors in baboon

A radiosynthetic method to prepare the nicotinic acetylcholine receptor radioligand (S)-5-[123I]iodo-3-(2-azetidinylmethoxy)pyridine, 5-IA, has been developed. The two-step sequence produced [123I]-5-IA in high radiochemical yield (52%), high radiochemical purity (98%), and high specific radioactivities (> 8,500 mCi/mumol). Preliminary single photon emission computed tomography studies with [123I]-5-IA in baboon demonstrated the appropriate regional localization for a high-affinity nicotinic radioprobe (thalamus > frontal cortex > cerebellum). Pretreatment with cytisine blocked [123I]-5-IA uptake in all brain regions (78-59% reduction), demonstrating the specificity of the radiotracer.     

Evaluation of 5-(11)C-methyl-A-85380 as an imaging agent for PET investigations of brain nicotinic acetylcholine receptors.

Central nicotinic acetylcholine receptors (nAChRs) represent major neurotransmitter receptors responsible for various brain functions, and changes in the density of nAChRs have recently been reported in several neurodegenerative diseases. Visualization of nAChRs in human brain has thus been of great interest, and the development of radiopharmaceuticals for the imaging and quantitative assessment of central nAChRs has been desired. In this study, we synthesized 5-(11)C-methyl-3-(2-(S)-azetidinylmethoxy)pyridine (5MA), a derivative of 3-(2-(S)-azetidinylmethoxy)pyridine (A-85380) (11)C-methylated at position 5 of the pyridyl fragment, and evaluated its potential for investigating central nAChRs by PET. METHODS: (11)C-5MA was synthesized by the incorporation of (11)C-methyl iodide into 5-butylstannyl A-85380, using a Pd-catalyzed coupling reaction. The affinity of 5MA for central nAChRs was measured by displacement of (-)-(3)H-cytisine from binding sites in rat cortical membranes. The biodistribution of (11)C-5MA was determined with mice. PET studies were performed on rhesus monkeys with a high-resolution PET scanner for animals. RESULTS: The overall synthesis time was 60 min from the end of radionuclide production, and the radiochemical yield, after purification by high-performance liquid chromatography, was 30%. The radiochemical purity of the product was >99%, with a specific radioactivity of >36 GBq/ micro mol. In vitro receptor-binding assays demonstrated that 5MA has a high, selective binding affinity for nAChRs, being approximately 1.5-fold higher than that of A-85380, 3.5-fold higher than that of (-)-cytisine, and 10-fold higher than that of (-)-nicotine. The distribution studies in mice showed that the brain uptake of (11)C-5MA was profound. Regional cerebral distribution studies in mice demonstrated that the accumulation of (11)C-5MA was consistent with the density of nAChRs, with the highest uptake observed in the thalamus, a moderate uptake in the cortex and striatum, and the lowest uptake in the cerebellum. Furthermore, preinjection of nAChR-binding ligands, (-)-nicotine and (-)-cytisine, reduced the uptake of (11)C-5MA in brain regions of high uptake in the untreated experiment. PET imaging studies with (11)C-5MA in rhesus monkeys demonstrated clear images consistent with the distribution of nAChRs in the brain. CONCLUSION: These results suggest that (11)C-5MA is a potential PET radiopharmaceutical for nuclear medical studies of nAChRs in the brain.     

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.     

In vivo imaging of human cerebral nicotinic acetylcholine receptors with 2-18F-fluoro-A-85380 and PET.

2-(18)F-fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine (2-(18)F-fluoro-A-85380) is a PET radioligand that is specific for nicotinic acetylcholine receptors (nAChRs) and has a high affinity for the alpha(4)beta(2) subtype. The purpose of this study was to evaluate different strategies to quantify 2-(18)F-fluoro-A-85380 binding in healthy nonsmoking human volunteers. METHODS: After intravenous injection of 189 +/- 30 MBq (0.8-5.7 nmol) of 2-(18)F-fluoro-A-85380, the first dynamic PET scan was acquired over 150 min. The second 30-min PET scan was performed 60 min later. Time-activity curves were generated from volumes of interest. 2-(18)F-Fluoro-A-85380 volume of distribution (DV) was quantified using compartmental kinetic analysis and Logan graphical analysis. In the kinetic analysis, the 1-tissue compartment model (1TCM) and the 2-tissue (2TCM) compartment model were applied. The most appropriate kinetic model was determined using the Akaike Information Criterion. The effect of reducing the PET study duration on the reliability of the DV values computed by the kinetic and the graphical analyses was evaluated. RESULTS: Time-activity curves were better described by the 2TCM. The DV values ranged from 5.2 +/- 0.5 in the occipital cortex, 6.2 +/- 0.2 in the frontal cortex, and 7.3 +/- 0.4 in the putamen to 15.4 +/- 2.1 in the thalamus. These regional DV values were consistent with the distribution of nAChRs in the human brain. Logan graphical analysis provided slightly lower DV values than those of the 2TCM (from -3.5% in the occipital cortex to -6.6% in the thalamus). The minimal study duration required to obtain stable DV estimates in all regions was similar for the 2 methods: 140 min for the 2TCM and 150 min for the Logan analysis. DV estimates obtained with the 2TCM were more stable than those calculated by the Logan approach for the same scan duration. CONCLUSION: These results show that 2-(18)F-fluoro-A-85380 can be used to assess nAChRs binding in the human brain with PET.     

5-[<Superscript>123</Superscript>I]Iodo-A-85380: assessment of pharmacological safety,radiation dosimetry and SPECT imaging of brain nicotinic receptors in healthy human subjects

Recently, 5-[123I]iodo-3-(2(S)-azetidinylmethoxy)pyridine ([123I]5IA) was developed as a ligand for imaging the nicotinic acetylcholine receptor (nAChR) in human brain using single photon emission computed tomography (SPECT). In the present study, the toxicity and radiation absorbed dose of [123I]5IA were investigated. Behavior and physiological parameters were examined in mice and rats after administration of 5IA. There were no changes in these parameters in animals administered 1 microg/kg of 5IA or less, indicating that the no observed effect level (NOEL) of 5IA was 1 microg/kg. [123I]5IA was then administered to healthy human subjects and serial whole-body images were acquired over 24 hr. Initially, high levels of radioactivity were observed in the liver and urinary bladder and moderate levels in the lungs, kidneys, and brain. Whole brain activity at 1 hr was 4.6 +/- 0.4% of the injected dose and this value gradually decreased with time. The majority (-75%) of the radioactivity was excreted in urine within 24 hr, and less than 1% remained in all organs tested. The biological half-life of [1231]51A averaged 7.2 +/- 4.0 hr. Based on the biodistribution data, radiation absorbed doses were estimated using MIRDOSE 3.1 software with the dynamic bladder model and the ICRP gastrointestinal (GI) tract model. Consequently, the effective dose equivalent was estimated to be 30 +/- 1.4 microSv/MBq, which is an acceptable radiation burden. Having determined the safety of this compound, we performed SPECT imaging in a healthy human subject using 171 MBq of [123I]5IA. SPECT images clearly revealed a cerebral distribution of radioactivity that was consistent with the known distribution of central nAChRs in humans. These results suggest that [123I]5IA is a promising ligand for imaging nAChRs in humans, with an acceptable dosimetry and pharmacological safety at the dose required for adequate SPECT imaging.     

Temporal change in human nicotinic acetylcholine receptor after smoking cessation: 5IA SPECT study.

Nicotinic acetylcholine receptors (nAChRs) are of great interest because they are implicated in various brain functions. They also are thought to play an important role in nicotine addiction of smokers. Chronic (-)-nicotine, a nAChR agonist, treatment in mice and rats elicits a dose-dependent increase in nAChRs in the brain. Upregulation of nAChRs in postmortem human brains of smokers has also been reported. However, changes in nAChRs after cigarette smoking cessation in humans are poorly understood. The aim of this study was to detect the dynamic changes of nAChRs after smoking and smoking cessation in the brains of living subjects. METHODS: We performed 5-(123)I-iodo-A-85380 ((123)I-5IA) SPECT on nonsmokers and smokers (n = 16) who had quit smoking for 4 h, 10 d, and 21 d and calculated and compared distribution volumes (Vt) of (123)I-5IA. RESULTS: The binding potential of nAChRs (Vt of (123)I-5IA) in the brains of smokers decreased by 33.5% +/- 10.5% after 4 h of smoking cessation, increased by 25.7% +/- 9.2% after 10 d of smoking cessation, and decreased to the level of nonsmokers after 21 d of smoking cessation. CONCLUSION: Because the upregulation of the nAChRs of the smokers after chronic exposure of the nicotine was downregulated to the nonsmokers' level by around 21 d after smoking cessation, the upregulation is a temporary effect. The decrease in nicotinic receptors to nonsmoker levels may be the breaking point during the nicotine withdrawal period.     

Alzheimer disease: quantitative analysis of I-123-iodoamphetamine SPECT brain imaging

To enable a more quantitative diagnosis of senile dementia of the Alzheimer type (SDAT), the authors developed and tested a semiautomated method to define regions of interest (ROIs) to be used in quantitating results from single photon emission computed tomography (SPECT) of regional cerebral blood flow performed with N-isopropyl iodine-123-iodoamphetamine. SPECT/IMP imaging was performed in ten patients with probable SDAT and seven healthy subjects. Multiple ROIs were manually and semiautomatically generated, and uptake was quantitated for each ROI. Mean cortical activity was estimated as the average of the mean activity in 24 semiautomatically generated ROIs; mean cerebellar activity was determined from the mean activity in separate ROIs. A ratio of parietal to cerebellar activity less than 0.60 and a ratio of parietal to mean cortical activity less than 0.90 allowed correct categorization of nine of ten and eight of ten patients, respectively, with SDAT and all control subjects. The degree of diminished mental status observed in patients with SDAT correlated with both global and regional changes in IMP uptake.     

Measurement of plasma metabolites of (S)-5-[123I]iodo-3-(2-azetidinylmethoxy)pyridine (5-IA-85380), a nicotinic acetylcholine receptor imaging agent, in nonhuman primates

The iodinated analog (S)-5-[123I]iodo-3-(2-azetidinylmethoxy)pyridine of A-85380 is a new potential SPECT tracer specific for the alpha4beta2 subtype nicotinic acetylcholine receptors, which play an important role in neurodegenerative diseases and in tobacco dependence. To evaluate the possibility of using this tracer for the in vivo quantification of these receptors, an accurate measurement of the plasma concentration of the parent compound is necessary. In human or nonhuman primate whole blood as well as in plasma, the parent compound is only stable for approximately 5 min, after which it decomposes. The radioligand is stable in the injection solution and in protein-free ( >30 K M.W.) plasma ultrafiltrate for at least 18 h. To preserve the parent compound in plasma the radioactive plasma must be mixed with equal volumes of acetonitrile within 5 min after its collection or, alternatively, radioactive blood should be collected and mixed with sodium azide (3 mg/ml blood). The in vivo metabolism of [123I]5-IA resulted in two components: a radiometabolite that is less lipophilic than the parent compound and a polar radiometabolite that is not free radioiodide because of the absence of radioactivity accumulation in the thyroid.     

Viable tissue in an area of severely reduced perfusion demonstrated with I-123 iomazenil brain SPECT imaging of benzodiazepine receptors.

A 70-year-old woman who experienced transient left hemiparesis had 90% stenosis of the right internal carotid artery. CT revealed small low-density areas in the subcortical frontal area. Baseline cerebral blood flow was reduced, and vasoreactivity was poor in the right frontoparietal area according to I-123 IMP brain SPECT with acetazolamide. The distribution of I-123 iomazenil was normal on the delayed SPECT image but reduced in the early SPECT image, mimicking baseline cerebral blood flow. The distribution of I-123 iomazenil SPECT on the delayed image reflected the normal binding potential of the benzodiazepine receptor and thus identified viable tissue in an area of severely reduced perfusion. These findings were confirmed by positron emission tomography.     

Equilibrium modeling of 5-ht2a receptors with [f]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.     

Unexpected detection of nodular melanoma of the skin on the scalp by I-123 IBZM brain SPECT

Melanocytes and dopaminergic neurons share the same ectodermal origin and can both produce melanin. Indeed, in vivo studies have shown that the radiopharmaceutical iodine-123-iodobenzamide (I-123 IBZM), which binds in vivo to dopamine D(2/3) receptors, is also able to detect melanoma, and particularly melanotic melanoma. We report a case of intense IBZM uptake in nodular melanoma of the skin on the scalp. The presence of unexpected focal IBZM uptake of the skin justified histologic examination, which revealed nodular melanoma. Melanoma should be considered when one is confronted with atypical focal uptake of benzamide derivatives like IBZM, in or outside the brain.     

Validation of an extracerebral reference region approach for the quantification of brain nicotinic acetylcholine receptors in squirrel monkeys with PET and 2-18F-fluoro-A-85380.

The aim of the present study was to explore the applicability of an extracerebral reference region for the quantification of cerebral receptors with PET. METHODS: Male squirrel monkeys underwent quantitative PET studies of cerebral nicotinic acetylcholine receptors (nAChRs) with 2-(18)F-fluoro-A-85380 (2-FA). Data from dynamic PET scans were analyzed with various compartment- and non-compartment-based models, including a simplified reference tissue model (SRTM). Nondisplaceable volume-of-distribution (VDnd) values were determined in regions of interest after the blockade of 2-FA-specific binding by nicotine infusion. Binding potential values, estimated with the cerebellum and muscle as reference regions, were compared and the reproducibility of measurements was determined. RESULTS: One- and 2-tissue-compartment modeling and linear graphic analysis provided similar total volume-of-distribution (VD(T)) values for each studied region. VD(T) values were high in the thalamus, intermediate in the cortex and midbrain, and low in the cerebellum and muscle, consistent with the distribution pattern of nAChR containing alpha(4) and beta(2) receptor subunits (alpha(4)beta(2)*). The administration of nicotine at 2 mg/kg/d via an osmotic pump resulted in a nearly complete saturation of 2-FA-specific binding and led to very small changes in volumes of distribution in the cerebellum and muscle (-9% +/- 4% [mean +/- SEM] and 0% +/- 6%, respectively), suggesting limited specific binding of the radioligand in these areas. VD(T) measured in muscle in 15 monkeys was reasonably constant (3.0 +/- 0.2, with a coefficient of variation of 8%). VDnd in studied brain regions exceeded VD(T) in muscles by a factor of 1.3. With this factor and with muscle as a reference region, BP* values calculated for studied brain regions with the SRTM were in good agreement with those obtained with the cerebellum as a reference region. Significant correlations were observed between BP* values estimated with these 2 approaches. The reproducibilities of BP* measurements obtained with the 2 methods were comparable, with coefficients of variation of less than 11% and 13% for the thalamus and the cortex, respectively. CONCLUSION: These results suggest that the accurate quantification of nAChRs can be performed with 2-FA and a reference region outside the brain, providing a novel approach for the quantification of brain receptors when no suitable cerebral reference region is available.     

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.     

Initial experience with SPECT imaging of the brain using I-123 p-iodoamphetamine in focal epilepsy

Nineteen patients with complex partial seizures refractory to medical treatment were examined with routine electroencephalography (EEG), video EEG monitoring, computed tomography or magnetic resonance imaging, neuropsychological tests and interictal single photon emission computed tomography (SPECT) with I-123 iodoamphetamine (INT). In 18 patients, SPECT identified areas of focal reduction in tracer uptake that correlated with the epileptogenic focus identified on the EEG. In addition, SPECT disclosed other areas of neurologic dysfunction as elicited on neuropsychological tests. Thus, IMP SPECT is a useful tool for localizing epileptogenic foci and their associated dynamic deficits.     

In vitro evaluation of nicotinic acetylcholine receptors with 2-[18F]F-A85380 in Parkinson's disease

Nicotinic acetylcholine receptors (nAChR) are involved in many physiological functions and appear to be affected in neurodegenerative diseases like Alzheimer's disease and Parkinson's disease (PD). Here, we describe the in vitro evaluation of nAChRs in PD with 2-[18F]F-A85380, a ligand with high affinity to the beta2 nAChR subunit. Autoradiography with 2-[18F]F-A85380 in untreated rat brain corresponded to the known distribution of alpha4beta2 nAChRs with high uptake in the thalamus, moderate uptake in the striatum and cortex and low uptake in the cerebellum (47%, 43% and 19% of the thalamus, respectively). The localization of alpha4beta2 nAChRs in the striatum was investigated in rodents with unilateral lesion of the substantia nigra. 2-[18F]F-A85380 binding was significantly reduced in the striatum ipsilateral to the lesion side (to 64% of the contralateral side), indicating that a fraction of alpha4beta2 nAChRs is located on dopaminergic terminals, whereas another fraction resides on striatal interneurons or cortical afferents. Similarly, in human brain sections of PD patients, 2-[18F]F-A85380 uptake was significantly reduced not only in the caudate and putamen but also in the thalamus (approximately 30% of the binding of control brain in all three regions); within the striatum, nAChRs in the putamen were significantly more severely affected as in the caudate. The observed pattern of alpha4beta2* nAChR loss demonstrates the potential of 2-[18F]F-A85380 for further investigations of this positron emission tomography ligand for in vivo studies of alpha4beta2* nAChRs in PD.