First-in-human imaging using [11C]MDTC: a radiotracer targeting the cannabinoid receptor type 2.

PURPOSE: We report findings from the first-in-human study of [11C]MDTC, a radiotracer developed to image the cannabinoid receptor type 2 (CB2R) with positron emission tomography (PET). METHODS: Ten healthy adults were imaged according to a 90-min dynamic PET protocol after bolus intravenous injection of [11C]MDTC. Five participants also completed a second [11C]MDTC PET scan to assess test-retest reproducibility of receptor-binding outcomes. The kinetic behavior of [11C]MDTC in human brain was evaluated using tissue compartmental modeling. Four additional healthy adults completed whole-body [11C]MDTC PET/CT to calculate organ doses and the whole-body effective dose. RESULTS: [11C]MDTC brain PET and [11C]MDTC whole-body PET/CT was well-tolerated. A murine study found evidence of brain-penetrant radiometabolites. The model of choice for fitting the time activity curves (TACs) across brain regions of interest was a three-tissue compartment model that includes a separate input function and compartment for the brain-penetrant metabolites. Regional distribution volume (VT) values were low, indicating low CB2R expression in the brain. Test-retest reliability of VT demonstrated a mean absolute variability of 9.91%. The measured effective dose of [11C]MDTC was 5.29 µSv/MBq. CONCLUSION: These data demonstrate the safety and pharmacokinetic behavior of [11C]MDTC with PET in healthy human brain. Future studies identifying radiometabolites of [11C]MDTC are recommended before applying [11C]MDTC PET to assess the high expression of the CB2R by activated microglia in human brain.

[18F]FNDP PET neuroimaging test-retest repeatability and whole-body dosimetry in humans.

PURPOSE: Soluble epoxide hydrolase (sEH) is an enzyme that shapes immune signaling through its role in maintaining the homeostasis of polyunsaturated fatty acids and their related byproducts. [18F]FNDP is a radiotracer developed for use with positron emission tomography (PET) to image sEH, which has been applied to imaging sEH in the brains of healthy individuals. Here, we report the test-retest repeatability of [18F]FNDP brain PET binding and [18F]FNDP whole-body dosimetry in healthy individuals. METHODS: Seven healthy adults (4 men, 3 women, ages 40.1 ± 4.6 years) completed [18F]FNDP brain PET on two occasions within a period of 14 days in a test-retest study design. [18F]FNDP regional total distribution volume (VT) values were derived from modeling time-activity data with a metabolite-corrected arterial input function. Test-retest variability, mean absolute deviation, and intraclass correlation coefficient (ICC) were investigated. Six other healthy adults (3 men, 3 women, ages 46.0 ± 7.0 years) underwent [18F]FNDP PET/CT for whole-body dosimetry, which was acquired over 4.5 h, starting immediately after radiotracer administration. Organ-absorbed doses and the effective dose were then estimated. RESULTS: The mean test-retest difference in regional VT (ΔVT) was 0.82 ± 5.17%. The mean absolute difference in regional VT was 4.01 ± 3.33%. The ICC across different brain regions ranged from 0.92 to 0.99. The organs with the greatest radiation-absorbed doses included the gallbladder (0.081 ± 0.024 mSv/MBq), followed by liver (0.077 ± 0.018 mSv/MBq) and kidneys (0.063 ± 0.006 mSv/MBq). The effective dose was 0.020 ± 0.003 mSv/MBq. CONCLUSION: These data support a favorable test-retest repeatability of [18F]FNDP brain PET regional VT. The radiation dose to humans from each [18F]FNDP PET scan is similar to that of other 18F-based PET radiotracers.

PET/CT imaging of CSF1R in a mouse model of tuberculosis.

PURPOSE: Macrophages represent an essential means of sequestration and immune evasion for Mycobacterium tuberculosis. Pulmonary tuberculosis (TB) is characterized by dense collections of tissue-specific and recruited macrophages, both of which abundantly express CSF1R on their outer surface. 4-Cyano-N-(5-(1-(dimethylglycyl)piperidin-4-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-2-yl)-1H-imidazole-2-carboxamide (JNJ-28312141) is a reported high affinity, CSF1R-selective antagonist. We report the radiosynthesis of 4-cyano-N-(5-(1-(N-methyl-N-([11C]methyl)glycyl)piperidin-4-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-2-yl)-1H-imidazole-2-carboxamide ([11C]JNJ-28312141) and non-invasive detection of granulomatous and diffuse lesions in a mouse model of TB using positron emission tomography (PET). METHODS: Nor-methyl-JNJ-28312141 precursor was radiolabeled with [11C]iodomethane to produce [11C]JNJ-28312141. PET/CT imaging was performed in the C3HeB/FeJ murine model of chronic pulmonary TB to co-localize radiotracer uptake with granulomatous lesions observed on CT. Additionally, CSF1R, Iba1 fluorescence immunohistochemistry was performed to co-localize CSF1R target with reactive macrophages in infected and healthy mice. RESULTS: Radiosynthesis of [11C]JNJ-28312141 averaged a non-decay-corrected yield of 18.7 ± 2.1%, radiochemical purity of 99%, and specific activity averaging 658 ± 141 GBq/µmol at the end-of-synthesis. PET/CT imaging in healthy mice showed hepatobiliary [13.39-25.34% ID/g, percentage of injected dose per gram of tissue (ID/g)] and kidney uptake (12.35% ID/g) at 40-50 min post-injection. Infected mice showed focal pulmonary lesion uptake (5.58-12.49% ID/g), hepatobiliary uptake (15.30-40.50% ID/g), cervical node uptake, and renal uptake (11.66-29.33% ID/g). The ratio of infected lesioned lung/healthy lung uptake is 5.91:1, while the ratio of lesion uptake to adjacent infected radiolucent lung is 2.8:1. Pre-administration of 1 mg/kg of unlabeled JNJ-28312141 with [11C]JNJ-28312141 in infected animals resulted in substantial blockade. Fluorescence microscopy of infected and uninfected whole lung sections exclusively co-localized CSF1R staining with abundant Iba1 + macrophages. Healthy lung exhibited no CSF1R staining and very few Iba1 + macrophages. CONCLUSION: [11C]JNJ-28312141 binds specifically to CSF1R + macrophages and delineates granulomatous foci of disease in a murine model of pulmonary TB.

PET imaging of microglia by targeting macrophage colony-stimulating factor 1 receptor (CSF1R).

While neuroinflammation is an evolving concept and the cells involved and their functions are being defined, microglia are understood to be a key cellular mediator of brain injury and repair. The ability to measure microglial activity specifically and noninvasively would be a boon to the study of neuroinflammation, which is involved in a wide variety of neuropsychiatric disorders including traumatic brain injury, demyelinating disease, Alzheimer's disease (AD), and Parkinson's disease, among others. We have developed [11C]CPPC [5-cyano-N-(4-(4-[11C]methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide], a positron-emitting, high-affinity ligand that is specific for the macrophage colony-stimulating factor 1 receptor (CSF1R), the expression of which is essentially restricted to microglia within brain. [11C]CPPC demonstrates high and specific brain uptake in a murine and nonhuman primate lipopolysaccharide model of neuroinflammation. It also shows specific and elevated uptake in a murine model of AD, experimental allergic encephalomyelitis murine model of demyelination and in postmortem brain tissue of patients with AD. Radiation dosimetry in mice indicated [11C]CPPC to be safe for future human studies. [11C]CPPC can be synthesized in sufficient radiochemical yield, purity, and specific radioactivity and possesses binding specificity in relevant models that indicate potential for human PET imaging of CSF1R and the microglial component of neuroinflammation.

First-in-human neuroimaging of soluble epoxide hydrolase using [18F]FNDP PET.

PURPOSE: Soluble epoxide hydrolase (sEH) is an enzyme with putative effect on neuroinflammation through its influence on the homeostasis of polyunsaturated fatty acids and related byproducts. sEH is an enzyme that metabolizes anti-inflammatory epoxy fatty acids to the corresponding, relatively inert 1,2-diols. A high availability or activity of sEH promotes vasoconstriction and inflammation in local tissues that may be linked to neuropsychiatric diseases. We developed [18F]FNDP to study sEH in vivo with positron emission tomography (PET). METHODS: Brain PET using bolus injection of [18F]FNDP followed by emission imaging lasting 90 or 180 min was completed in healthy adults (5 males, 2 females, ages 40-53 years). The kinetic behavior of [18F]FNDP was evaluated using a radiometabolite-corrected arterial plasma input function with compartmental or graphical modeling approaches. RESULTS: [18F]FNDP PET was without adverse effects. Akaike information criterion favored the two-tissue compartment model (2TCM) in all ten regions of interest. Regional total distribution volume (VT) values from each compartmental model and Logan analysis were generally well identified except for corpus callosum VT using the 2TCM. Logan analysis was assessed as the choice model due to stability of regional VT values from 90-min data and due to high correlation of Logan-derived regional VT values with those from the 2TCM. [18F]FNDP binding was higher in human cerebellar cortex and thalamus relative to supratentorial cortical regions, which aligns with reported expression patterns of the epoxide hydrolase 2 gene in human brain. CONCLUSION: These data support further use of [18F]FNDP PET to study sEH in human brain.

In Vitro and In Vivo Characterization of Dibenzothiophene Derivatives [125I]Iodo-ASEM and [18F]ASEM as Radiotracers of Homo- and Heteromeric α7 Nicotinic Acetylcholine Receptors.

The α7 nicotinic acetylcholine receptor (α7 nAChR) is involved in several cognitive and physiologic processes; its expression levels and patterns change in neurologic and psychiatric diseases, such as schizophrenia and Alzheimer's disease, which makes it a relevant drug target. Development of selective radioligands is important for defining binding properties and occupancy of novel molecules targeting the receptor. We tested the in vitro binding properties of [125I]Iodo-ASEM [(3-(1,4-diazabycyclo[3.2.2]nonan-4-yl)-6-(125I-iododibenzo[b,d]thiopentene 5,5-dioxide)] in the mouse, rat and pig brain using autoradiography. The in vivo binding properties of [18F]ASEM were investigated using positron emission tomography (PET) in the pig brain. [125I]Iodo-ASEM showed specific and displaceable high affinity (~1 nM) binding in mouse, rat, and pig brain. Binding pattern overlapped with [125I]α-bungarotoxin, specific binding was absent in α7 nAChR gene-deficient mice and binding was blocked by a range of α7 nAChR orthosteric modulators in an affinity-dependent order in the pig brain. Interestingly, relative to the wild-type, binding in ß2 nAChR gene-deficient mice was lower for [125I]Iodo-ASEM (58% ± 2.7%) than [125I]α-bungarotoxin (23% ± 0.2%), potentially indicating different binding properties to heteromeric α7ß2 nAChR. [18F]ASEM PET in the pig showed high brain uptake and reversible tracer kinetics with a similar spatial distribution as previously reported for α7 nAChR. Blocking with SSR-180,711 resulted in a significant decrease in [18F]ASEM binding. Our findings indicate that [125I]Iodo-ASEM allows sensitive and selective imaging of α7 nAChR in vitro, with better signal-to-noise ratio than previous tracers. Preliminary data of [18F]ASEM in the pig brain demonstrated principal suitable kinetic properties for in vivo quantification of α7 nAChR, comparable to previously published data.

Opportunities in precision psychiatry using PET neuroimaging in psychosis.

With the movement toward precision medicine in healthcare, recent studies of individuals with psychosis have begun to explore positron emission tomography (PET) as a tool to test for biochemical signatures that may distinguish subtypes of psychosis that guide subtype-specific therapeutic interventions. This review presents selected PET findings that exemplify early promise in using molecular imaging to predict treatment response, provide rationale for new therapeutic targets, and monitor target engagement in biomarker-defined subtypes of psychosis. PET data, among other data types, may prove useful in the scientific pursuit of identifying precision strategies to improve clinical outcomes for individuals with psychosis.

Radiosynthesis and validation of [5-cyano-N-(4-(4-[11 C]methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl) furan-2-carboxamide] ([11 C]CPPC), a PET radiotracer for imaging CSF1R, a microglia-specific marker.

In this practitioner protocol, the radiochemical synthesis of [11 C]CPPC is described in detail, and a quality control summary of three validation productions is presented. The results indicate that the radiotracer product can be produced in good radiochemical yield (> 60 mCi (2.22 GBq) at end-of-synthesis (EOS)), at high specific activity (molar activity > 11,435 mCi/µmole (423 GBq/µmole) at EOS) and high chemical and radiochemical purity. The entire production conforms to current Good Manufacturing Practice (cGMP) requirements. The final product is formulated as a sterile, pyrogen-free solution suitable for human injection.

Brain PET Imaging of α7-nAChR with [18F]ASEM: Reproducibility, Occupancy, Receptor Density, and Changes in Schizophrenia.

Background: The α7 nicotinic acetylcholine receptor increasingly has been implicated in normal brain physiology, as well as in neuropsychiatric disorders. The highly cortical distribution of α7 nicotinic acetylcholine receptor suggests a role in cognition. Methods: We expanded the first-in-human PET imaging of α7 nicotinic acetylcholine receptor with [18F]ASEM from 5 to 21 healthy nonsmoking volunteers and added a feasibility study in 6 male patients with schizophrenia. Study aims included: (1) confirmation of test-retest reproducibility of [18F]ASEM binding, (2) demonstration of specificity by competition with DMXB-A, an α7 nicotinic acetylcholine receptor partial agonist, (3) estimation of [18F]ASEM binding potentials and α7 nicotinic acetylcholine receptor density in vivo in humans, and (4) demonstrating the feasibility of studying α7 nicotinic acetylcholine receptor as a target for schizophrenia. Results: Test-retest PET confirmed reproducibility (>90%) (variability ≤7%) of [18F]ASEM volume of distribution (VT) estimates in healthy volunteers. Repeated sessions of PET in 5 healthy subjects included baseline and effect of inhibition after oral administration of 150 mg DMXB-A. From reduction of binding potentials, we estimated the dose-dependent occupancy of α7 nicotinic acetylcholine receptor by DMXB-A at 17% to 49% for plasma concentrations at 60 to 200 nM DMXB-A. In agreement with evidence postmortem, α7 nicotinic acetylcholine receptor density averaged 0.67 to 0.82 nM and inhibitor affinity constant averaged 170 to 385 nM. Median VT in a feasibility study of 6 patients with schizophrenia was lower than in healthy volunteers in cingulate cortex, frontal cortex, and hippocampus (P = 0.02, corrected for multiple comparions, Mann-Whitney test). Conclusions: The current results confirm the reproducibility of [18F]ASEM VT estimates and the specificity of the tracer for α7 nicotinic acetylcholine receptor. Preliminary findings from our feasibility study of [18F]ASEM binding in patients with schizophrenia are suggestive and provide guidance for future studies with more subjects.

An optimized radiosynthesis of [18 F]FNDP, a positron emission tomography radiotracer for imaging soluble epoxide hydrolase (sEH).

In this concise practitioner protocol, the radiochemical synthesis of [18 F]FNDP suitable for human positron emission tomography studies is described and the results from validation productions are presented. The high specific activity radiotracer product is prepared as a sterile, apyrogenic solution that conforms to current Good Manufacturing Practice requirements.

Synthesis and Preliminary Biological Evaluation of Indol-3-yl-oxoacetamides as Potent Cannabinoid Receptor Type 2 Ligands.

A small series of indol-3-yl-oxoacetamides was synthesized starting from the literature known N-(adamantan-1-yl)-2-(5-(furan-2-yl)-1-pentyl-1H-indol-3-yl)-2-oxoacetamide (5) by substituting the 1-pentyl-1H-indole subunit. Our preliminary biological evaluation showed that the fluorinated derivative 8 is a potent and selective CB2 ligand with Ki = 6.2 nM.

AT-1001 Is a Partial Agonist with High Affinity and Selectivity at Human and Rat α3ß4 Nicotinic Cholinergic Receptors.

AT-1001 [N-(2-bromophenyl)-9-methyl-9-azabicyclo[3.3.1] nonan-3-amine] is a high-affinity and highly selective ligand at α3ß4 nicotinic cholinergic receptors (nAChRs) that was reported to decrease nicotine self-administration in rats. It was initially reported to be an antagonist at rat α3ß4 nAChRs heterologously expressed in HEK293 cells. Here we compared AT-1001 actions at rat and human α3ß4 and α4ß2 nAChRs similarly expressed in HEK 293 cells. We found that, as originally reported, AT-1001 is highly selective for α3ß4 receptors over α4ß2 receptors, but its binding selectivity is much greater at human than at rat receptors, because of a higher affinity at human than at rat α3ß4 nAChRs. Binding studies in human and rat brain and pineal gland confirmed the selectivity of AT-1001 for α3ß4 nAChRs and its higher affinity for human compared with rat receptors. In patch-clamp electrophysiology studies, AT-1001 was a potent partial agonist with 65-70% efficacy at both human and rat α3ß4 nAChRs. It was also a less potent and weaker (18%) partial agonist at α4ß2 nAChRs. Both α3ß4 and α4ß2 nAChRs are upregulated by exposure of cells to AT-1001 for 3 days. Similarly, AT-1001 desensitized both receptor subtypes in a concentration-dependent manner, but it was 10 and 30 times more potent to desensitize human α3ß4 receptors than rat α3ß4 and human α4ß2 receptors, respectively. After exposure to AT-1001, the time to recovery from desensitization was longest for the human α3ß4 nAChR and shortest for the human α4ß2 receptor, suggesting that recovery from desensitization is primarily related to the dissociation of the ligand from the receptor.

Microwave-assisted radiosynthesis of [(18) F]ASEM, a radiolabeled α7-nicotinic acetylcholine receptor antagonist.

An improvement of the original radiochemical synthesis of [(18) F]ASEM, an α7-nicotinic acetylcholinergic receptor radioligand, is reported. The new procedure utilizes microwave-assisted radiofluorination. In addition, a new preparative HPLC method was developed to eliminate a chemical impurity in the final product. Quality control procedures were also enhanced to improve detection of product with enhanced resolution of potential impurities. [(18) F]ASEM was produced in 20.1 ± 8.9% non-decay corrected (NDC) yield with an average synthesis time of 57 min and an average specific radioactivity of 856 ± 332 GBq/µmol (23 ± 9 Ci/µmol).

Exploring [11C]CPPC as a CSF1R-targeted PET Imaging Marker for Early Parkinson's Disease Severity.

Neuroinflammation through enhanced innate immunity is thought play a role in the pathogenesis of Parkinson's disease (PD). Methods for monitoring neuroinflammation in living patients with PD are currently limited to positron emission tomography (PET) ligands that lack specificity in labeling immune cells in the nervous system. The colony stimulating factor 1 receptor (CSF1R) plays a crucial role in microglial function, an important cellular contributor to the nervous system's innate immune response. Using immunologic methods, we show that CSF1R in human brain is colocalized with the microglial marker, ionized calcium binding adaptor molecule 1 (Iba1). In PD, CSF1R immunoreactivity is significantly increased in PD across multiple brain regions, with the largest differences in the midbrain versus controls. Autoradiography revealed significantly increased [3H]JHU11761 binding in the inferior parietal cortex of PD patients. PET imaging demonstrated that higher [11C]CPPC binding in the striatum was associated with greater motor disability in PD. Furthermore, increased [11C]CPPC binding in various regions correlated with more severe motor disability and poorer verbal fluency. This study finds that CSF1R expression is elevated in PD and that [11C]CPPC-PET imaging of CSF1R is indicative of motor and cognitive impairments in the early stages of the disease. Moreover, the study underscores the significance of CSF1R as a promising biomarker for neuroinflammation in Parkinson's disease, suggesting its potential use for non-invasive assessment of disease progression and severity, leading to earlier diagnosis and targeted interventions.

Recent PET radioligands with optimal brain kinetics for imaging nicotinic acetylcholine receptors.

Cerebral neuronal nicotinic acetylcholine receptors (nAChRs) are implicated in various neurophysiological processes and in the pathophysiology and/or treatment strategies of various disorders. Positron emission tomography (PET) imaging of nAChR and, especially, the most prominent cerebral subtype α4ß2-nAChR is important in smoking, epilepsy, attention deficit hyperactivity disorder, depression, schizophrenia, cognition, behavior, memory, and in research involving aging, cognitive impairments, and dementia. Most human α4ß2-nAChR PET imaging has been performed with 2-[(18) F]FA, but slow brain kinetics is the substantial drawback of 2-[(18) F]FA that precludes widespread PET imaging research of nAChR in humans. Development of a better PET radioligand for α4ß2-nAChR was a focus of substantial investigation that has been thoroughly reviewed (up to 2009) previously. This article attempts to summarize the peer-reviewed publications of the most recent development and preclinical studies of novel α4ß2-nAChR PET radioligands with improved brain kinetics and first human studies with one of these radioligands ([(18) F]AZAN).

Pilot imaging of the colony stimulating factor 1 receptor in the brains of virally-suppressed individuals with HIV.

OBJECTIVE: Neuroimmune activation is a putative driver of cognitive impairment in people with HIV (PWH), even in the age of modern antiretroviral therapy. Nevertheless, imaging of the microglial marker, the 18 kDa translocator protein (TSPO), with positron emission tomography (PET) in treated PWH has yielded inconclusive findings. One potential reason for the varied TSPO results is a lack of cell-type specificity of the TSPO target. DESIGN: [ 11 C]CPPC, 5-cyano- N -(4-(4-[ 11 C]methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl) furan-2-carboxaminde, is a radiotracer for use with PET to image the colony stimulating factor 1 receptor (CSF1R). The CSF1R is expressed on microglia and central nervous system macrophages, with little expression on other cell types. We used [ 11 C]CPPC PET in virally-suppressed- (VS)-PWH and HIV-uninfected individuals to estimate the effect sizes of higher CSF1R in the brains of VS-PWH. METHODS: Sixteen VS-PWH and 15 HIV-uninfected individuals completed [ 11 C]CPPC PET. [ 11 C]CPPC binding (V T ) in nine regions was estimated using a one-tissue compartmental model with a metabolite-corrected arterial input function, and compared between groups. RESULTS: Regional [ 11 C]CPPC V T did not significantly differ between groups after age- and sex- adjustment [unstandardized beta coefficient ( B ) = 1.84, standard error (SE) = 1.18, P  = 0.13]. The effect size was moderate [Cohen's d  = 0.56, 95% confidence interval (CI) -0.16, 1.28), with strongest trend of higher V T in VS-PWH in striatum and parietal cortex (each P  = 0.04; Cohen's d  = 0.71 and 0.72, respectively). CONCLUSIONS: A group difference in [ 11 C]CPPC V T was not observed between VS-PWH and HIV-uninfected individuals in this pilot, although the observed effect sizes suggest the study was underpowered to detect regional group differences in binding.

Positron emission tomography experience with 2-[¹8F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[¹8F]FA) in the living human brain of smokers with paranoid schizophrenia.

Utilizing postmortem data (Breese et al. [2000] Neuropsychopharmacology 23:351-364), we hypothesized that the densities of high-affinity neuronal α4ß2 nicotinic acetylcholine receptors (nAChRs) in the brain exist in a continuum from highest to lowest as follows: smokers without schizophrenia > smokers with schizophrenia > nonsmokers without schizophrenia > nonsmokers with schizophrenia. Application of the Kruskal-Wallis Test (Statacorp, 2003) to the postmortem data (Breese et al. [2000] Neuropsychopharmacology 23:351-364) confirmed the hypothesized order in the cortex and the hippocampus and attained significance in the caudate and the thalamus. Positron emission tomography (PET) was performed for 60 min at 6 h after the intravenous administration of 444 megabequerels [MBq] (12 mCi) 2-[¹8F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[¹8F]FA), a radiotracer for high-affinity neuronal α4ß2 nAChRs, as a bolus plus continuous infusion to 10 adults (seven men and three women) (six smokers including five with paranoid schizophrenia and four nonsmokers) ranging in age from 22 to 56 years (mean 40.1, standard deviation 13.6). The thalamic nondisplaceable binding potential (BP(ND) ) was 1.32 ± 0.19 (mean ± standard deviation) for healthy control nonsmokers; 0.50 ± 0.19 for smokers with paranoid schizophrenia; and 0.51 for the single smoker without paranoid schizophrenia. The thalamic BP(ND) s of nonsmokers were significantly higher than those of smokers who smoked cigarettes a few hours before the scans (P = 0.0105) (StataCorp, 2003), which was likely due to occupancy of nAChRs by inhaled nicotine in smokers. Further research is needed to rule out the effects of confounding variables.

5-(5-(6-[(11)C]methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)pyridin-2-yl)-1H-indole as a potential PET radioligand for imaging cerebral α7-nAChR in mice.

The radiosynthesis and in vivo evaluation of 5-(5-(6-[(11)C]methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)pyridin-2-yl)-1H-indole [(11)C]rac-(1), a potential PET tracer for α7 nicotinic acetylcholine receptors (α7-nAChR), are described. Syntheses of the nonradioactive standard rac-1 and corresponding desmethyl precursor 7 were achieved in several reaction steps. Radiomethylation of 7 with [(11)C]CH(3)I afforded [(11)C]rac-1 in an average radiochemical yield of 30 ± 5% (n=5) with high radiochemical purity and an average specific radioactivity of 444 ± 74 GBq/µmol (n=5). The total synthesis time was 30 min from end-of-bombardment. Biodistribution studies in mice showed that [(11)C]rac-1 penetrates the blood-brain barrier and specifically labels neuronal α7-nAChRs.

First-in-human use of 11C-CPPC with positron emission tomography for imaging the macrophage colony-stimulating factor 1 receptor.

PURPOSE: Study of the contribution of microglia to onset and course of several neuropsychiatric conditions is challenged by the fact that these resident immune cells often take on different phenotypes and functions outside the living brain. Imaging microglia with radiotracers developed for use with positron emission tomography (PET) allows researchers to study these cells in their native tissue microenvironment. However, many relevant microglial imaging targets such as the 18 kDa translocator protein are also expressed on non-microglial cells, which can complicate the interpretation of PET findings. 11C-CPPC was developed to image the macrophage colony-stimulating factor 1 receptor, a target that is expressed largely by microglia relative to other cell types in the brain. Our prior work with 11C-CPPC demonstrated its high, specific uptake in brains of rodents and nonhuman primates with neuroinflammation, which supports the current first-in-human evaluation of its pharmacokinetic behavior in the brains of healthy individuals. METHODS: Eight healthy nonsmoker adults completed a 90-min dynamic PET scan that began with bolus injection of 11C-CPPC. Arterial blood sampling was collected in order to generate a metabolite-corrected arterial input function. Tissue time-activity curves (TACs) were generated using regions of interest identified from co-registered magnetic resonance imaging data. One- and two-tissue compartmental models (1TCM and 2TCM) as well as Logan graphical analysis were compared. RESULTS: Cortical and subcortical tissue TACs peaked by 37.5 min post-injection of 11C-CPPC and then declined. The 1TCM was preferred. Total distribution volume (VT) values computed from 1TCM aligned well with those from Logan graphical analysis (t* = 30), with VT values relatively high in thalamus, striatum, and most cortical regions, and with relatively lower VT in hippocampus, total white matter, and cerebellar cortex. CONCLUSION: Our results extend support for the use of 11C-CPPC with PET to study microglia in the human brain.

Synthesis and in vivo evaluation of (S)-6-(4-fluorophenoxy)-3-((1-[11C]methylpiperidin-3-yl)methyl)-2-o-tolylquinazolin-4(3H)-one, a potential PET tracer for growth hormone secretagogue receptor (GHSR).

The peptide hormone ghrelin mediates through action on its receptor, the growth hormone secretagogue receptor (GHSR), and is known to play an important role in a variety of metabolic functions including appetite stimulation, weight gain, and suppression of insulin secretion. In light of the fact that obesity is one of the major health problems plaguing the modern society, the ghrelin signaling system continues to remain an important and attractive pharmacological target for the treatment of obesity. In vivo imaging of the GHSR could shed light on the mechanism by which ghrelin affects feeding behavior and thus offers a new therapeutic perspective for the development of effective treatments. Recently, a series of piperidine-substituted quinazolinone derivatives was reported to be selective and potent GHSR antagonists with high binding affinities. Described herein is the synthesis, in vitro, and in vivo evaluation of (S)-6-(4-fluorophenoxy)-3-((1-[(11)C]methylpiperidin-3-yl)methyl)-2-o-tolylquinazolin-4(3H)-one ([(11)C]1), a potential PET radioligand for imaging GHSR.