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Preclinical evaluation of [ <sup>18</sup> F]MA3, a CB <sub/>2</sub> receptor agonist radiotracer for Positron Emission Tomography
摘要： Background and Purpose: Non-invasive in vivo imaging of CB2 receptors (CB2R) using positron emission tomography (PET) is pursued to study neuroinflammation. The purpose of this study is to evaluate the in vivo binding specificity of [18F]MA3, a CB2R agonist, in a rat model with local overexpression of human CB2R (hCB2R). Methods: [18F]MA3 was produced with good radiochemical yield and radiochemical purity. The radiotracer was evaluated in rats with local overexpression of hCB2R and in a healthy non-human primate using PET. Key results: Ex vivo autoradiography demonstrated CB2 specific binding of [18F]MA3 in rat hCB2R vector injected striatum. In a PET study, increased tracer binding in the hCB2R vector injected striatum compared to the contralateral control vector injected striatum was observed. Binding in hCB2R vector injected striatum was blocked with a structurally non related CB2R inverse agonist and a displacement study confirmed the reversibility of tracer binding. This study identified the utility of mutated inactive vector model for evaluation of CB2R agonist PET tracers. [18F]MA3 PET scans in the non-human primate showed good uptake and fast wash out from brain, but no CB2 specific binding was observed. Conclusion and Implications: Evaluation of [18F]MA3 in a rat model with local overexpression of hCB2R showed CB2 specific and reversible tracer binding. [18F]MA3 showed good brain uptake and subsequent wash out in a healthy non-human primate but no specific binding was observed. Further clinical evaluation of [18F]MA3 in patients with neuroinflammation is warranted.
关键词： CB2R,PET imaging,neuroinflammation,[18F]MA3,radiotracer
更新于2025-09-23 15:22:29
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Development and <i>in vivo</i> evaluation of a novel kappa opioid receptor agonist as PET radiotracer with superior imaging characteristics
摘要： Studies have shown kappa opioid receptor (KOR) abnormalities in addictive disorders, other central nervous system diseases and Alzheimer’s disease. We have developed the first set of agonist 11C-GR103545 and antagonist 11C-LY2795050 radiotracers for positron emission tomography imaging of KOR in human. Nonetheless, 11C-GR103545 displays protracted uptake kinetics and is not an optimal radiotracer. Here we report the development and evaluation of 11C-EKAP and its comparison with 11C-GR103545. Methods: EKAP was synthesized and assayed for in vitro binding affinities, then radiolabeled with 11C-CH3OTf. PET studies were carried out in rhesus monkeys. Blocking studies were performed with naloxone and the selective KOR antagonists LY2795050 and LY2456302. Arterial input functions were generated for use in kinetic modeling. Brain time-activity curves were analyzed with the multilinear analysis 1 (MA1) method to derive binding parameters. Results: EKAP has high KOR affinity (Ki = 0.28 nM) and good selectivity in vitro. 11C-EKAP was prepared in good radiochemical purity. 11C-EKAP rapidly metabolized in plasma, and displayed fast and reversible kinetics in brain with peak uptake at < 20 min post-injection. Pre-blocking with naloxone (1 mg/kg) or LY2795050 (0.2 mg/kg) produced 84-89% receptor occupancy, while LY2456302 (0.05 & 0.3 mg/kg) dose-dependently reduced 11C-EKAP specific binding, thus demonstrating its binding specificity and selectivity in vivo. Mean MA1-derived BPND values were 1.74, 1.79, 1.46, 0.80 and 0.77 for cingulate cortex, globus pallidus, insula, striatum and frontal cortex, consistent with the known KOR distribution in primate brains. Conclusions: We have successfully developed 11C-EKAP as a novel KOR agonist tracer with dual attractive imaging properties of fast uptake kinetics and high specific binding in vivo.
关键词： 11C-EKAP,PET radiotracer,agonist,non-human primates,kappa opioid receptor
更新于2025-09-23 15:22:29
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Handbook of Neuro-Oncology Neuroimaging || Positron Emission Tomography (PET) and Single-Photon Emission Computed Tomography (SPECT) Physics
摘要： The purpose of emission tomography is to estimate the distribution of a radiotracer from external measurements of the pattern of photons emerging from the brain. Some of these photons are detected, and certain information about them recorded, by the scanner. These external measurements are termed “projections,” and each measurement in a projection represents, ideally, the sum of radioactivity concentration along a line through the brain. From these measured projection data sets and knowledge of certain aspects of the single-photon emission computed tomography (SPECT) or positron emission tomography (PET) instrument, estimated images of the distribution of radioactivity are mathematically reconstructed. All modern SPECT and PET scanners image the three-dimensional (3D) distribution of radioactivity, either as a stack of two-dimensional (2D) transaxial images or directly as a 3D volume.
关键词： Single-Photon Emission Computed Tomography,Positron Emission Tomography,Image Reconstruction,Radiotracer,SPECT,PET,Radioactivity Distribution,Physics
更新于2025-09-23 15:21:01
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In vivo comparison of N-11CH3 vs O-11CH3 radiolabeled microtubule targeted PET ligands
摘要： Altered dynamics of microtubules (MT) are implicated in the pathophysiology of a number of brain diseases. Therefore, radiolabeled MT targeted ligands that can penetrate the blood brain barrier (BBB) may offer a direct and sensitive approach for diagnosis, and assessing the clinical potential of MT targeted therapeutics using PET imaging. We recently reported two BBB penetrating radioligands, [11C]MPC-6827 and [11C]HD-800 as specific PET ligands for imaging MTs in brain. The major metabolic pathway of the above molecules is anticipated to be via the initial labeling site, O-methyl, compared to the N-methyl group. Herein, we report the radiosynthesis of N-11CH3-MPC-6827 and N-11CH3-HD-800 and a comparison of their in vivo binding with the corresponding O-11CH3 analogues using microPET imaging and biodistribution methods. Both O-11CH3 and N-11CH3 labeled MT tracers exhibit high specific binding and brain. The N-11CH3 labeled PET ligands demonstrated similar in vivo binding characteristics compared with the corresponding O-11CH3 labeled tracers, [11C]MPC-6827 and [11C]HD-800 respectively.
关键词： brain,PET,microtubule,tubulin,radiotracer
更新于2025-09-16 10:30:52
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Past and Present of Imaging Modalities Used for Prostate Cancer Diagnosis: Androgen Receptor Targeted Imaging of Prostate Cancer as a Future Modality for Early, Rapid and Efficient Diagnosis
摘要： Background: Prostate cancer is the second most prevailing cancer among men worldwide. In the most cases, prostate cancer is slowly progressing, whereas, in some cases, it is a rapidly progressing disease leading to the significantly high mortality rate. Thus, there is still demand for prostate-specific imaging in order to provide image-guided early diagnosis and for the provision of patient-specific therapy. Discussion: Besides discussing traditional diagnostic approaches, this review illustrates a perspective on prostate cancer imaging summarizing current imaging approaches with a special focus on Prostate Specific Membrane Antigen (PSMA), Bombesin (BN) and Androgen Receptor (AR) targeted imaging using Positron Emission Tomography (PET) and Single Positron Emission Computed Tomography (SPECT) based on 99mTc and other radiotracers. Here, the prostate biology is reconsidered for nuclear imaging as future modality for early, rapid and efficient diagnosis of prostate cancer. Conclusion: Future direction in prostate cancer imaging involves the development of androgen receptor based imaging using nonsteroidal antiandrogen agent for early diagnosis of prostate cancer.
关键词： single photon emission computed tomography,Prostate cancer,patient-specific therapy,radiotracer,positron-emission tomography,prostate-specific membrane antigen
更新于2025-09-09 09:28:46
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Synthesis and evaluation of 4-(2-fluoro-4-[11C]methoxyphenyl)-5-((2-methylpyridin-4-yl)methoxy)picolinamide for PET imaging of the metabotropic glutamate receptor 2 in the rat brain
摘要： Metabotropic glutamate receptor 2 (mGluR2) has been suggested as a therapeutic target for treating schizophrenia-like symptoms arising from increased glutamate transmission in the human forebrain. However, no reliable positron emission tomography (PET) radiotracer allowing for in vivo visualization of mGluR2 in the human brain is currently available. In this study, we synthesized 4-(2-fluoro-4-[11C]methoxyphenyl)-5-((2-methylpyridin-4-yl)methoxy)picolinamide ([11C]1) and evaluated its potential as a PET tracer for imaging mGluR2 in the rodent brain. Compound 1, a negative allosteric modulator (NAM) of mGluR2, showed high in vitro binding affinity (IC50: 26 nM) for mGluR2 overexpressed in human cells. [11C]1 was synthesized by O-[11C]methylation of the phenol precursor 2 with [11C]methyl iodide. After the reaction, HPLC purification and formulation, [11C]1 of 7.4 ± 2.8 GBq (n = 8) was obtained from [11C]carbon dioxide of 22.5 ± 4.8 GBq (n = 8) with >99% radiochemical purity and 70 ± 32 GBq/μmol (n = 8) molar activity at the end of synthesis. In vitro autoradiography for rat brains showed that [11C]1 binding was heterogeneously distributed in the cerebral cortex, striatum, hippocampus, and cerebellum. This pattern is consistent with the regional distribution pattern of mGluR2 in the rodent brain. The radioactivity was significantly reduced by self- or MNI-137 (a mGluR2 NAM) blocking. Small-animal PET studies indicated a low in vivo specific binding of [11C]1 in the rat brain. The brain uptake was increased in a P-glycoprotein and breast cancer resistant protein double knockout mouse, when compared to a wild-type mouse. While [11C]1 presented limited potential as an in vivo PET tracer for mGluR2, we suggested that it can be used as a lead compound for developing new radiotracers with improved in vivo brain properties.
关键词： positron emission tomography,radiotracer,schizophrenia,metabotropic glutamate receptor 2,in vitro autoradiography
更新于2025-09-04 15:30:14