[en] The α_7 nicotinic acetylcholine receptor (nAChR) is implicated in many neuropsychiatric disorders, making it an important target for positron emission tomography (PET) imaging. The first aim of this work was to compare two α_7 nAChRs PET radioligands, ["1"8F]ASEM 3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-(["1"8F]fluorodibenzo[b,d]thiophene 5,5-dioxide) and ["1"8F]DBT-10 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-(["1"8F]fluorodibenzo[b,d]thiophene 5,5-dioxide), in nonhuman primates. The second aim was to assess further the quantification and test-retest variability of ["1"8F]ASEM in humans. PET scans with high specific activity ["1"8F]ASEM or ["1"8F]DBT-10 were acquired in three rhesus monkeys (one male, two female), and the kinetic properties of these radiotracers were compared. Additional ["1"8F]ASEM PET scans with blocking doses of nicotine, varenicline, and cold ASEM were acquired separately in two animals. Next, six human subjects (five male, one female) were imaged with ["1"8F]ASEM PET for 180 min, and arterial sampling was used to measure the parent input function. Different modeling approaches were compared to identify the optimal analysis method and scan duration for quantification of ["1"8F]ASEM distribution volume (V_T). In addition, retest scans were acquired in four subjects (three male, one female), and the test-retest variability of V_T was assessed. In the rhesus monkey brain ["1"8F]ASEM and ["1"8F]DBT-10 exhibited highly similar kinetic profiles. Dose-dependent blockade of ["1"8F]ASEM binding was observed, while administration of either nicotine or varenicline did not change ["1"8F]ASEM V_T. ["1"8F]ASEM was selected for further validation because it has been used in humans. Accurate quantification of ["1"8F]ASEM V_T in humans was achieved using multilinear analysis with at least 90 min of data acquisition, resulting in V_T values ranging from 19.6 ± 2.5 mL/cm"3 in cerebellum to 25.9 ± 2.9 mL/cm"3 in thalamus. Test-retest variability of V_T was 11.7 ± 9.8%. These results confirm ["1"8F]ASEM as a suitable radiotracer for the imaging and quantification of α_7 nAChRs in humans. (orig.)

[en] To quantify the synaptic vesicle glycoprotein 2A (SV2A) changes in the whole central nervous system (CNS) under pathophysiological conditions, a high affinity SV2A PET radiotracer with improved in vivo stability is desirable to minimize the potential confounding effect of radiometabolites. The aim of this study was to develop such a PET tracer based on the molecular scaffold of UCB-A, and evaluate its pharmacokinetics, in vivo stability, specific binding, and nonspecific binding signals in nonhuman primate brains, in comparison with [${}^{11}$C]UCB-A, [${}^{11}$C]UCB-J, and [${}^{18}$F]SynVesT-1. The racemic SDM-16 (4-(3,5-difluorophenyl)-1-((2-methyl-1H-imidazol-1-yl)methyl)pyrrolidin-2-one) and its two enantiomers were synthesized and assayed for in vitro binding affinities to human SV2A. We synthesized the enantiopure [${}^{18}$F]SDM-16 using the corresponding enantiopure arylstannane precursor. Nonhuman primate brain PET scans were performed on FOCUS 220 scanners. Arterial blood was drawn for the measurement of plasma free fraction ($f_P$), radiometabolite analysis, and construction of the plasma input function. Regional time-activity curves (TACs) were fitted with the one-tissue compartment (1TC) model to obtain the volume of distribution (V${}_T$). Nondisplaceable binding potential (BP${}_{ND}$) was calculated using either the nondisplaceable volume of distribution (V_{ND}$)orthecentrumsemiovale(CS)asthereferenceregion.SDM-<!--\; ???\; -->16wassynthesizedin3stepswith44$_i$ = 0.9 nM) to human SV2A among all reported SV2A ligands. [${}^{18}$F]SDM-16 was prepared in about 20% decay-corrected radiochemical yield within 90 min, with greater than 99% radiochemical and enantiomeric purity. This radiotracer displayed high specific binding in monkey brains and was metabolically more stable than the other SV2A PET tracers. The $f_P$ of [${}^{18}$F]SDM-16 was 69%, which was higher than those of [${}^{11}$C]UCB-J (46%), [${}^{18}$F]SynVesT-1 (43%), [${}^{18}$F]SynVesT-2 (41%), and [${}^{18}$F]UCB-H (43%). The TACs were well described with the 1TC. The averaged test-retest variability (TRV) was 7 ± 3%, and averaged absolute TRV (aTRV) was 14 ± 7% for the analyzed brain regions. We have successfully synthesized a novel SV2A PET tracer [${}^{18}$F]SDM-16, which has the highest SV2A binding affinity and metabolical stability among published SV2A PET tracers. The [${}^{18}$F]SDM-16 brain PET images showed superb contrast between gray matter and white matter. Moreover, [${}^{18}$F]SDM-16 showed high specific and reversible binding in the NHP brains, allowing for the reliable and sensitive quantification of SV2A, and has potential applications in the visualization and quantification of SV2A beyond the brain.

[en] Currently, there are multiple active clinical trials involving poly(ADP-ribose) polymerase (PARP) inhibitors in the treatment of glioblastoma. The noninvasive quantification of baseline PARP expression using positron emission tomography (PET) may provide prognostic information and lead to more precise treatment. Due to the lack of brain-penetrant PARP imaging agents, the reliable and accurate in vivo quantification of PARP in the brain remains elusive. Herein, we report the synthesis of a brain-penetrant PARP PET tracer, (R)-2-(2-methyl-1-(methyl-${}^{11}$C)pyrrolidin-2-yl)-1H-benzo[d]imidazole-4-carboxamide ([${}^{11}$C]PyBic), and its preclinical evaluations in a syngeneic RG2 rat glioblastoma model and healthy nonhuman primates. We synthesized [${}^{11}$C]PyBic using veliparib as the labeling precursor, performed dynamic PET scans on RG2 tumor-bearing rats and calculated the distribution volume ratio (DVR) using simplified reference region method 2 (SRTM2) with the contralateral nontumor brain region as the reference region. We performed biodistribution studies, western blot, and immunostaining studies to validate the in vivo PET quantification results. We characterized the brain kinetics and binding specificity of [${}^{11}$C]PyBic in nonhuman primates on FOCUS220 scanner and calculated the volume of distribution (V${}_T$), nondisplaceable volume of distribution (V${}_{ND}$), and nondisplaceable binding potential (BP${}_{ND}$) in selected brain regions. [${}^{11}$C]PyBic was synthesized efficiently in one step, with greater than 97% radiochemical and chemical purity and molar activity of 148 ± 85 MBq/nmol (n = 6). [${}^{11}$C]PyBic demonstrated PARP-specific binding in RG2 tumors, with 74% of tracer binding in tumors blocked by preinjected veliparib (i.v., 5 mg/kg). The in vivo PET imaging results were corroborated by ex vivo biodistribution, PARP1 immunohistochemistry and immunoblotting data. Furthermore, brain penetration of [${}^{11}$C]PyBic was confirmed by quantitative monkey brain PET, which showed high specific uptake (BP${}_{ND}$ > 3) and low nonspecific uptake (V${}_{ND}$< 3 mL/cm${}^3$) in the monkey brain. [${}^{11}$C]PyBic is the first brain-penetrant PARP PET tracer validated in a rat glioblastoma model and healthy nonhuman primates. The brain kinetics of [${}^{11}$C]PyBic are suitable for noninvasive quantification of available PARP binding in the brain, which posits [${}^{11}$C]PyBic to have broad applications in oncology and neuroimaging.

[en] 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.

[en] Introduction: GR103545 is a potent and selective kappa-opioid receptor agonist. Previous studies in non-human primates demonstrated favorable properties of [¹¹C]GR103545 as a positron emission tomography tracer for in vivo imaging of cerebral kappa-opioid receptor. Nonetheless, advancement of [¹¹C]GR103545 to imaging studies in humans was hampered by difficulties of its multiple-step radiosynthesis, which produces a final product with low specific activity (SA), which in turn could induce undesirable physiological side effects resulting from the mass associated with an injected amount of radioactivity. We report herein an alternative radiosynthesis of [¹¹C]GR103545 with higher SA and radiochemical yields. Methods: The TRACERLab FXC automated synthesis module was used to carry out the two-step, one-pot procedure. In the first step, the desmethoxycarbonyl precursor was converted to the carbamic acid intermediate desmethyl-GR103545 via transcarboxylation with the zwitterionic carbamic complex, 1,8-diazabicyclo[5.4.0]undec-7-ene-carbon dioxide, in the presence and/or absence of cesium carbonate and tetrabutylammonium triflate. In the second step, the intermediate was radiolabeled at the carboxyl oxygen with [¹¹C]methyl trifluoromethanesulfonate to give [¹¹C]GR103545. Results: This novel synthesis produced [¹¹C]GR103545 with ≥90% chemical and radiochemical purities and an SA of 290.45±99.9 MBq/nmol at the end of synthesis (n=26). Injectable radioactivity was 1961±814 GBq/μmol with 43 min of average synthesis time from the end of beam. Conclusion: We have developed a practical one-pot method for the routine production of [¹¹C]GR103545 with reliably high SA and radiochemical yield, thus allowing the advancement of this radiotracer to imaging applications in humans.

[en] 

Purpose

To determine if one venous blood sample can substitute full arterial sampling in quantitative modeling for multiple positron emission tomography (PET) radiotracers using simultaneous estimation of the input function (SIME).

Procedures

Participants underwent PET imaging with [¹¹C]ABP688, [¹¹C]CUMI-101, and [¹¹C]DASB. Full arterial sampling and additional venous blood draws were performed for quantification with the arterial input function (AIF) and SIME using one arterial or venous (vSIME) sample.

Results

Venous and arterial metabolite-corrected plasma activities were within 6 % of each other at varying time points. vSIME- and AIF-derived outcome measures were in good agreement, with optimal sampling times of 12 min ([¹¹C]ABP688), 90 min ([¹¹C]CUMI-101), and 100 min ([¹¹C]DASB). Simulation-based power analyses revealed that SIME required fewer subjects than the AIF method to achieve statistical power, with significant reductions for [¹¹C]CUMI-101 and [¹¹C]DASB with vSIME. Replication of previous findings and test-retest analyses bolstered the simulation analyses.

Conclusions

We demonstrate the feasibility of AIF recovery using SIME with one venous sample for [¹¹C]ABP688, [¹¹C]CUMI-101, and [¹¹C]DASB. This method simplifies PET acquisition while allowing for fully quantitative modeling, although some variability and bias are present with respect to AIF-based quantification, which may depend on the accuracy of the single venous blood measurement.

[en] Exploring synaptic density changes during brain growth is crucial to understanding brain development. Previous studies in nonhuman primates report a rapid increase in synapse number between the late gestational period and the early neonatal period, such that synaptic density approaches adult levels by birth. Prenatal synaptic development may have an enduring impact on postnatal brain development, but precisely how synaptic density changes in utero are unknown because current methods to quantify synaptic density are invasive and require post-mortem brain tissue. We used synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) radioligands [${}^{11}$C]UCB-J and [${}^{18}$F]Syn-VesT-1 to conduct the first assessment of synaptic density in the developing fetal brain in gravid rhesus monkeys. Eight pregnant monkeys were scanned twice during the third trimester at two imaging sites. Fetal post-mortem samples were collected near term in a subset of subjects to quantify SV2A density by Western blot. Image-derived fetal brain SV2A measures increased during the third trimester. SV2A concentrations were greater in subcortical regions than in cortical regions at both gestational ages. Near term, SV2A density was higher in primary motor and visual areas than respective associative regions. Post-mortem quantification of SV2A density was significantly correlated with regional SV2A PET measures. While further study is needed to determine the exact relationship of SV2A and synaptic density, the imaging paradigm developed in the current study allows for the effective in vivo study of SV2A development in the fetal brain.

[en] Introduction: Erlotinib is a tyrosine kinase inhibitor prescribed for non-small cell lung cancer (NSCLC) patients bearing epidermal growth factor receptor mutations in the kinase domain. The objectives of this study were to (1) establish a human dosimetry profile of [¹¹C]erlotinib and (2) assess the consistency of calculated equivalent dose across species using the same dosimetry model. Methods: Subjects examined in this multi-species study included: a stage IIIa NSCLC patient, 3 rhesus macaque monkeys, a landrace pig, and 4 athymic nude-Fox1nu mice. [¹¹C]erlotinib PET data of the whole body were acquired dynamically for up to 120 min. Regions of interest (ROIs) were manually drawn to extract PET time activity curves (TACs) from identifiable organs. TACs were used to calculate time-integrated activity coefficients (residence times) in each ROI, which were then used to calculate the equivalent dose in OLINDA. Subject data were used to predict the equivalent dose to the organs of a 73.7 kg human male. Results: In three of four species, the liver was identified as the organ receiving the highest equivalent dose (critical organ). The mean equivalent doses per unit of injected activity to the liver based on human, monkey, and mouse data were 29.4 μSv/MBq, 17.4 ± 6.0 μSv/MBq, and 5.27 ± 0.25 μSv/MBq, respectively. The critical organ based on the pig data was the gallbladder wall (20.4 μSv/MBq) but the liver received a nearly identical equivalent dose (19.5 μSv/MBq). Conclusions: (1) When designing PET studies using [¹¹C]erlotinib, the liver should be considered the critical organ. (2) In organs receiving the greatest equivalent dose, mouse data underestimated the dose in comparison to larger species. However, the effective dose of [¹¹C]erlotinib to the whole body of a 73.7 kg man was predicted with good consistency based on mice (3.14 ± 0.05 μSv/MBq) or the larger species (3.46 ± 0.25 μSv/MBq).

[en] Aging is a major societal concern due to age-related functional losses. Synapses are crucial components of neural circuits, and synaptic density could be a sensitive biomarker to evaluate brain function. [${}^{11}$C]UCB-J is a positron emission tomography (PET) ligand targeting synaptic vesicle glycoprotein 2A (SV2A), which can be used to evaluate brain synaptic density in vivo. We evaluated age-related changes in gray matter synaptic density, volume, and blood flow using [${}^{11}$C]UCB-J PET and magnetic resonance imaging (MRI) in a wide age range of 80 cognitive normal subjects (21-83 years old). Partial volume correction was applied to the PET data. Significant age-related decreases were found in 13, two, and nine brain regions for volume, synaptic density, and blood flow, respectively. The prefrontal cortex showed the largest volume decline (4.9% reduction per decade: RPD), while the synaptic density loss was largest in the caudate (3.6% RPD) and medial occipital cortex (3.4% RPD). The reductions in caudate are consistent with previous SV2A PET studies and likely reflect that caudate is the site of nerve terminals for multiple major tracts that undergo substantial age-related neurodegeneration. There was a non-significant negative relationship between volume and synaptic density reductions in 16 gray matter regions. MRI and [${}^{11}$C]-UCB-J PET showed age-related decreases of gray matter volume, synaptic density, and blood flow; however, the regional patterns of the reductions in volume and SV2A binding were different. Those patterns suggest that MR-based measures of GM volume may not be directly representative of synaptic density.