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The aim of this study was to examine the suitability of [18 F]nifene, a novel α4β2* nicotinic acetylcholine receptor (nAChR) radiotracer, for in vivo brain imaging in a first-in-human study. Eight healthy subjects (4 M,4 F;21-69,44 ± 21 yrs) underwent a [18 F]nifene positron emission tomography scan (200 ± 3.7 MBq), and seven underwent a second scan within 58 ± 31 days. Regional estimates of DVR were measured using the multilinear reference tissue model (MRTM2) with the corpus callosum as reference region. DVR reproducibility was evaluated with test-retest variability (TRV) and intraclass correlation coefficient (ICC). The DVR ranged from 1.3 to 2.5 across brain regions with a TRV of 0-7%, and did not demonstrate a systematic difference between test and retest. The ICCs ranged from 0.2 to 0.9. DVR estimates were stable after 40 min. The binding profile and tracer kinetics of [18 F]nifene make it a promising α4β2* nAChR radiotracer for scientific research in humans, with reliable DVR test-retest reproducibility.

The neuropeptide oxytocin is part of a neuroendocrine system that has physiological effects ranging from ensuring uterine myometrial contractions at parturition and post-partum mammary gland milk ejection to the modulation of neural control of social relationships. This initial study was performed to investigate the potential use of positron emission tomography (PET) for localizing oxytocin receptors in two New World primates. Three biomarkers for PET (1-3) that are known to have high affinity and selectivity for the human oxytocin receptor were investigated in the common marmoset (Callithrix jacchus) via PET imaging. Brain penetration, and uptake in the salivary gland area were both observed with biomarkers 2 and 3. No brain penetration was observed with 1, but uptake was observed more specifically in several peripheral endocrine glands compared to 2 or 3. Biomarker 2, which displayed the best brain penetration of the three biomarkers in the marmoset, was then investigated in the monogamous coppery titi monkey (Callicebus cupreus) in a brain scan and a limited full body scan. No significant brain penetration of 2 was observed in the titi monkey, but significant uptake was observed in various locations throughout the periphery. Metabolism of 2 was suspected to have been significant based upon HPLC analysis of blood draws, but parent compound was still present near the end of the scan. Follow-up investigations will focus on next generation biomarkers bearing improved binding characteristics and brain penetrability as well as investigating tissue in regions where biomarker uptake was observed.

UnlabelledThe serotonin-1A (5-HT1A; 5-HT is 5-hydroxytryptamine) receptor is implicated in an array of neurologic and psychiatric disorders. Current PET radioligands targeting 5-HT1A receptors have limitations hindering widespread PET studies of this receptor system. The 5-HT1A-specific antagonist radioligand N-{2-[4-(2-methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(trans-4-(18)F-fluoromethylcyclohexane)carboxamide ((18)F-mefway) exhibited promising in vivo properties in rhesus monkeys. The goal of this work was to examine the in vivo cerebral binding profile and metabolism of (18)F-mefway in humans.MethodsDynamic (18)F-mefway PET data were acquired for 6 healthy volunteers (4 women, 2 men; age, 22-38 y). Scans were initiated with the injection of 192-204 MBq of radiotracer, and data were acquired for 2 h. Venous blood samples were collected and assayed to examine the in vivo metabolism profile of (18)F-mefway. To examine the test-retest variability of (18)F-mefway, a second PET scan was acquired at least 2 wk later for 4 subjects. Regional binding potentials (BPNDs) were calculated with the multilinear reference tissue model, and voxelwise BPND maps were calculated with Logan graphical analysis. Regions surrounding the brain were carefully inspected for uptake of radiolabeled species in bone.Results(18)F-mefway uptake in the brain occurred quickly, with a peak standardized uptake value (SUV) of 1.7. Rapid washout in the cerebellum resulted in SUVs of 0.2 at 120 min, whereas regions with specific 5-HT1A binding exhibited retention of radioligand, yielding SUVs of 0.4-0.9 at 120 min. Rapid metabolism of (18)F-mefway was observed, with no detected (18)F-fluoride ions in plasma. BPND values of 2.4 were measured in the mesial temporal lobe, with values of 1.6 in the insular cortex and 0.7-1.0 in other cortical regions. Stable BPND estimates were obtained using 90 min of dynamic data. Average test-retest variability was 8%. No evidence of radioactivity uptake in bone was observed.Conclusion(18)F-mefway exhibits favorable in vivo properties for serotonin 5-HT1A receptor measurements in humans. The simple radiosynthesis, high specific binding profile, and absence of PET signal in bone make (18)F-mefway an attractive radiotracer for PET experiments examining the 5-HT1A receptor in neuropsychiatric disorders and drug intervention.

4-trans-[(18)F]Mefway is a PET radiotracer with high affinity for 5-HT1A receptors. Our preliminary work indicated the positional isomer, 3-[(18)F]mefway, would be suitable for PET imaging of 5-HT1A receptors. We now compare the in vivo behaviour of 3-mefway with 4-mefway to evaluate 3-[(18)F]mefway as a potential 5-HT1A PET radiotracer. Two male rhesus macaques were given bolus injections of both 3- and 4-trans-[(18)F]mefway in separate experiments. 90 minute dynamic PET scans were acquired. TACs were extracted in the mesial temporal lobe (MTL) and caudal anterior cingulate gyrus (cACg). The cerebellum (CB) was used as a reference region. In vivo behavior of the radiotracers in the CB was compared based upon the ratio of normalized PET uptake for 3- and 4-trans-[(18)F]mefway. Specific binding was compared by examining MTL/CB and cACg/CB ratios. The subject-averaged ratio of 3-[(18)F]mefway to 4-trans-[(18)F]mefway in the cerebellum was 0.96 for 60-90 minutes. MTL/CB reached plateaus of ~2.7 and ~6 by 40 minutes and 90 minutes for 3- and 4-trans-[(18)F]mefway, respectively. cACg/CB reached plateaus of ~2.5 and ~6 by 40 minutes and 70 minutes for 3- and 4-trans-[(18)F]mefway, respectively. The short pseudoequilibration times and sufficient uptake of 3-[(18)F]mefway may be useful in studies requiring short scan times. Furthermore, the similar nondisplaceable clearance in the CB to 4-trans-[(18)F]mefway suggests the lower BPND of 3-[(18)F]mefway is due to a lower affinity. The lower affinity of 3-[(18)F]mefway may make it useful for measuring changes in endogenous 5-HT levels, however, this remains to be ascertained.

The development of inert, biocompatible chelation methods is required to harness the emerging positron emitting radionuclide 45Ti for radiopharmaceutical applications. Herein, we evaluate the Ti(IV)‐coordination chemistry of four catechol‐based, hexacoordinate chelators using synthetic, structural, computational, and radiochemical approaches. The siderophore enterobactin (Ent) and its synthetic mimic TREN‐CAM readily form mononuclear Ti(IV) species in aqueous solution at neutral pH. Radiolabeling studies reveal that Ent and TREN‐CAM form mononuclear complexes with the short‐lived, positron‐emitting radionuclide 45Ti(IV), and do not transchelate to plasma proteins in vitro and exhibit rapid renal clearance in naïve mice. These features guide efforts to target the 45Ti isotope to prostate cancer tissue through the design, synthesis, and evaluation of Ent‐DUPA, a small molecule conjugate composed of a prostate specific membrane antigen (PSMA) targeting peptide and a monofunctionalized Ent scaffold. The [45Ti][Ti(Ent‐DUPA)]2− complex forms readily at room temperature. In a tumor xenograft model in mice, selective tumor tissue accumulation (8±5 %, n=5), and low off‐target uptake in other organs is observed. Overall, this work demonstrates targeted imaging with 45Ti(IV), provides a foundation for advancing the application of 45Ti in nuclear medicine, and reveals that Ent can be repurposed as a 45Ti‐complexing cargo for targeted nuclear imaging applications. [ABSTRACT FROM AUTHOR]

The development of inert, biocompatible chelation methods is required to harness the emerging positron emitting radionuclide 45Ti for radiopharmaceutical applications. Herein, we evaluate the Ti(IV)‐coordination chemistry of four catechol‐based, hexacoordinate chelators using synthetic, structural, computational, and radiochemical approaches. The siderophore enterobactin (Ent) and its synthetic mimic TREN‐CAM readily form mononuclear Ti(IV) species in aqueous solution at neutral pH. Radiolabeling studies reveal that Ent and TREN‐CAM form mononuclear complexes with the short‐lived, positron‐emitting radionuclide 45Ti(IV), and do not transchelate to plasma proteins in vitro and exhibit rapid renal clearance in naïve mice. These features guide efforts to target the 45Ti isotope to prostate cancer tissue through the design, synthesis, and evaluation of Ent‐DUPA, a small molecule conjugate composed of a prostate specific membrane antigen (PSMA) targeting peptide and a monofunctionalized Ent scaffold. The [45Ti][Ti(Ent‐DUPA)]2− complex forms readily at room temperature. In a tumor xenograft model in mice, selective tumor tissue accumulation (8±5 %, n=5), and low off‐target uptake in other organs is observed. Overall, this work demonstrates targeted imaging with 45Ti(IV), provides a foundation for advancing the application of 45Ti in nuclear medicine, and reveals that Ent can be repurposed as a 45Ti‐complexing cargo for targeted nuclear imaging applications. [ABSTRACT FROM AUTHOR]

Acetylcholinesterase inhibitors (AChEIs) are drugs that increase synaptic acetylcholine (ACh) concentrations and are under investigation as treatments for symptoms accompanying Alzheimer's disease. The goal of this work was to use PET imaging to evaluate alterations of in vivo α4β2 nicotinic acetylcholine receptor (nAChR) binding induced by the AChEIs physostigmine (PHY) and galanthamine (GAL). The α4β2 nAChR-specific radioligand [(18)F]nifene was used to examine the effects of 0.1-0.2 mg/kg PHY, 5 mg/kg GAL, and saline in three separate experiments all performed on each of two rat subjects. A 60-min bolus-infusion protocol was used with drug administered after 30 min. Data from the thalamus and cortex were analyzed with a graphical model accounting for neurotransmitter activation using the cerebellum as a reference region to test for transient competition with bound [(18) F]nifene. Significant [(18) F]nifene displacement was detected in both regions during one PHY and both GAL studies, while no significant competition was observed in both saline studies. This preliminary work indicates the viability of [(18) F]nifene in detecting increases in synaptic ACh induced by AChEIs.

[(18)F]Nifene is an agonist PET radioligand developed to image α4β2* nicotinic acetylcholine receptors (nAChRs). This work aims to quantify the receptor density (Bmax) of α4β2* nAChRs and the in vivo (apparent) dissociation constant (KDapp) of [(18)F]nifene. Multiple-injection [(18)F]nifene experiments with varying cold nifene masses were conducted on four rhesus monkeys with a microPET P4 scanner. Compartment modeling techniques were used to estimate regional Bmax values and a global value of KDapp. The fast kinetic properties of [(18)F]nifene also permitted alternative estimates of Bmax and KDapp at transient equilibrium with the same experimental data using Scatchard-like methodologies. Averaged across subjects, the compartment modeling analysis yielded Bmax values of 4.8±1.4, 4.3±1.0, 1.2±0.4, and 1.2±0.3 pmol/mL in the regions of antereoventral thalamus, lateral geniculate, frontal cortex, and subiculum, respectively. The KDapp of nifene was 2.4±0.3 pmol/mL. The Scatchard analysis based on graphical evaluation of the data after transient equilibrium yielded Bmax estimations comparable to the modeling results with a positive bias of 28%. These findings show the utility of [(18)F]nifene for measuring α4β2* nAChR Bmax in vivo in the rhesus monkey with a single PET experiment.

The therapeutic efficacy of photodynamic therapy is limited by the ability of light to penetrate tissues. Due to this limitation, Cerenkov luminescence (CL) from radionuclides has recently been proposed as an alternative light source in a strategy referred to as Cerenkov radiation‐induced therapy (CRIT). Semiconducting polymer nanoparticles (SPNs) have ideal optical properties, such as large absorption cross‐sections and broad absorbance, which can be utilized to harness the relatively weak CL produced by radionuclides. SPNs can be doped with photosensitizers and have ≈100% energy transfer efficiency by multiple energy transfer mechanisms. Herein, an optimized photosensitizer‐doped SPN is investigated as a nanosystem to harness and amplify CL for cancer theranostics. It is found that semiconducting polymers significantly amplify CL energy transfer efficiency. Bimodal positron emission tomography (PET) and optical imaging studies show high tumor uptake and retention of the optimized SPNs when administered intravenously or intratumorally. Lastly, it is found that photosensitizer‐doped SPNs have excellent potential as a cancer theranostics nanosystem in an in vivo tumor therapy study. This study shows that SPNs are ideally suited to harness and amplify CL for cancer theranostics, which may provide a significant advancement for CRIT that are unabated by tissue penetration limits. [ABSTRACT FROM AUTHOR]

Background: Neuronal hypometabolism measured with [18F]FDG PET scans can be used to identify neurodegeneration as part of the AT(N) (amyloid, tau, neurodegeneration) framework in AD. PET imaging of synaptic vesicle glycoprotein SV2A using [11C]UCB‐J provides an index of synaptic density, which has been shown to decrease during neurodegeneration. The purpose of this study was to examine the regional relationship between neuronal metabolism and synaptic density in participants across the continuum of AD‐related pathology. Method: Participants were recruited from the Wisconsin ADRC and the Wisconsin Registry for Alzheimer's Prevention (WRAP) study. A subset of 13 participants (Table 1) were selected who had completed cognitive testing, structural MR imaging, and PET imaging with the following: [11C]PiB centiloid (CL) for amyloid +/‐ status, [18F]MK‐6240 SUVR for tau +/‐ status, [11C]UCB‐J DVR for regional synaptic density burden, and [18F]FDG SUVR for regional glucose metabolism. UCB‐J and FDG analysis used a whole cerebellum reference region; PiB and MK‐6240 analysis used cerebellar GM reference regions. Inter‐tracer (UCB‐J/FDG) correlations were performed in Freesurfer‐defined bilateral Braak‐associated ROIs (Medial Temporal Lobe [MTL]: entorhinal cortex, hippocampus, and amygdala; Ventral Temporal Lobe [VTL]: fusiform, lingual, and inferior temporal gyri), signature regions of hypometabolism in AD (posterior cingulate, parietal, and frontal cortices) and a region with only marginal hypometabolism in AD (occipital cortex). Associations were determined using Pearson correlations (r). Result: All ROIs demonstrate a positive association between FDG SUVR and UCB‐J DVR, with r > 0.7 and p < 0.01 (Figure 1). The occipital, frontal, and posterior cingulate cortices demonstrate the strongest correlations (r = 0.84, 0.83, and 0.81, respectively). Conclusion: In cognitively impaired and unimpaired participants showing varying degrees of β‐amyloid and neurofibrillary tau burden, strong positive correlations are observed in regions associated with AD tau pathology and hypometabolism. Correlations are also observed in regions not typically associated with hypometabolism. This suggests that a relationship may exist between synaptic density and neuronal metabolism in the presence of AD neuropathology. [ABSTRACT FROM AUTHOR]

Background: The extent to which amyloid‐β burden and neurofibrillary tau tangle burden are associated with synaptic degeneration in vivo is not well known. PET imaging was used to examine the cross‐sectional relationship between neurofibrillary tau tangle burden and amyloid‐β plaque burden with synaptic density among individuals who spanned the clinical and biologic Alzheimer's disease continuum. Method: Participants were recruited from the Wisconsin Alzheimer's Disease Research Center and the Wisconsin Registry for Alzheimer's Prevention study. N = 64 participants were included in the analysis based on completed cognitive testing, structural MR and PET imaging using [11C]PiB DVR for amyloid burden, [18F]MK‐6240 SUVR for regional neurofibrillary tau burden, and [11C]UCB‐J DVR for regional synaptic density burden analysis. Amyloid burden was indexed as a global [11C]PiB DVR representing the mean of brain regions that typically accumulate amyloid. UCB‐J DVR and MK‐6240 SUVR regions of interest were selected based on the histopathological staging of tau pathology in Alzheimer's disease with a focus on regions of tau pathology described by earlier and later Braak stages. The first composite region of interest (ROI1) comprised the hippocampus and entorhinal cortex, and the second (ROI2) comprised the amygdala, fusiform, lingual gyrus, and the inferior temporal gyrus. Linear correlations (Pearson's r) tested the relationship between UCB‐J DVR and PiB DVR, as well as UCB‐J DVR and MK‐6240 SUVR. Result: Global [11C]PiB DVR showed a moderate negative relationship with UCB‐J DVR in ROI1 (r = ‐0.42, p = 0.0006) and a weak relationship with UCB‐J DVR in ROI2 (r = ‐0.33, p = 009). [18F]MK‐6240 SUVR and UCB‐J DVR were negatively correlated in ROI1 (r = ‐0.44, p = 0.0003) and in ROI2 (r = ‐0.42, p = 0.005). Conclusion: Both amyloid burden and tau pathology were associated with lower synaptic density. Tau and synaptic density appeared to show moderate correlations among brain regions involved in both earlier and more advanced tau pathology, whereas amyloid burden appeared to be more strongly related to synaptic density in brain regions where more advanced disease is typically observed. [ABSTRACT FROM AUTHOR]

Background: Neuronal hypometabolism measured with [18F]FDG PET scans can be used to identify neurodegeneration as part of the AT(N) (amyloid, tau, neurodegeneration) framework in AD. PET imaging of synaptic vesicle glycoprotein SV2A using [11C]UCB‐J provides an index of synaptic density, which has been shown to decrease during neurodegeneration. The purpose of this study was to examine the regional relationship between neuronal metabolism and synaptic density in participants across the continuum of AD‐related pathology. Method: Participants were recruited from the Wisconsin ADRC and the Wisconsin Registry for Alzheimer's Prevention (WRAP) study. A subset of 13 participants (Table 1) were selected who had completed cognitive testing, structural MR imaging, and PET imaging with the following: [11C]PiB centiloid (CL) for amyloid +/‐ status, [18F]MK‐6240 SUVR for tau +/‐ status, [11C]UCB‐J DVR for regional synaptic density burden, and [18F]FDG SUVR for regional glucose metabolism. UCB‐J and FDG analysis used a whole cerebellum reference region; PiB and MK‐6240 analysis used cerebellar GM reference regions. Inter‐tracer (UCB‐J/FDG) correlations were performed in Freesurfer‐defined bilateral Braak‐associated ROIs (Medial Temporal Lobe [MTL]: entorhinal cortex, hippocampus, and amygdala; Ventral Temporal Lobe [VTL]: fusiform, lingual, and inferior temporal gyri), signature regions of hypometabolism in AD (posterior cingulate, parietal, and frontal cortices) and a region with only marginal hypometabolism in AD (occipital cortex). Associations were determined using Pearson correlations (r). Result: All ROIs demonstrate a positive association between FDG SUVR and UCB‐J DVR, with r > 0.7 and p < 0.01 (Figure 1). The occipital, frontal, and posterior cingulate cortices demonstrate the strongest correlations (r = 0.84, 0.83, and 0.81, respectively). Conclusion: In cognitively impaired and unimpaired participants showing varying degrees of ß‐amyloid and neurofibrillary tau burden, strong positive correlations are observed in regions associated with AD tau pathology and hypometabolism. Correlations are also observed in regions not typically associated with hypometabolism. This suggests that a relationship may exist between synaptic density and neuronal metabolism in the presence of AD neuropathology. [ABSTRACT FROM AUTHOR]