Molecular imaging with positron emission tomography (PET) and single photon emission computed tomography (SPECT) is a well-established and important in vivo technique to evaluate fundamental ...biological processes and unravel the role of neurotransmitter receptors in various neuropsychiatric disorders. Specific ligands are available for PET/SPECT studies of dopamine, serotonin, and opiate receptors, but corresponding development of radiotracers for receptors of glutamate, the main excitatory neurotransmitter in mammalian brain, has lagged behind. This state of affairs has persisted despite the central importance of glutamate neurotransmission in brain physiology and in disorders such as stroke, epilepsy, schizophrenia, and neurodegenerative diseases. Recent years have seen extensive efforts to develop useful ligands for molecular imaging of subtypes of the ionotropic (
-methyl-
-aspartate (NMDA), kainate, and AMPA/quisqualate receptors) and metabotropic glutamate receptors (types I, II, and III mGluRs). We now review the state of development of radioligands for glutamate receptor imaging, placing main emphasis on the suitability of available ligands for reliable in vivo applications. We give a brief account of the radiosynthetic approach for selected molecules. In general, with the exception of ligands for the GluN2B subunit of NMDA receptors, there has been little success in developing radiotracers for imaging ionotropic glutamate receptors; failure of ligands for the PCP/MK801 binding site in vivo doubtless relates their dependence on the open, unblocked state of the ion channel. Many AMPA and kainite receptor ligands with good binding properties in vitro have failed to give measurable specific binding in the living brain. This may reflect the challenge of developing brain-penetrating ligands for amino acid receptors, compounded by conformational differences in vivo. The situation is better with respect to mGluR imaging, particularly for the mGluR5 subtype. Several successful PET ligands serve for investigations of mGluRs in conditions such as schizophrenia, depression, substance abuse and aging. Considering the centrality and diversity of glutamatergic signaling in brain function, we have relatively few selective and sensitive tools for molecular imaging of ionotropic and metabotropic glutamate receptors. Further radiopharmaceutical research targeting specific subtypes and subunits of the glutamate receptors may yet open up new investigational vistas with broad applications in basic and clinical research.
The folate receptor-α (FR-α) is overexpressed in many epithelial cancers, including ovary, uterus, kidneys, breast, lung, colon and prostate carcinomas, but shows limited expression in normal tissues ...such as kidneys, salivary glands, choroid plexus and placenta. FR-α has therefore emerged as a promising target for the delivery of therapeutic and imaging agents to FR-positive tumors. A series of folate-based PET (positron emission tomography) radiopharmaceuticals have been developed for the selective targeting of FR-positive malignancies. This review provides an overview on the research progress made so far regarding the design, radiosynthesis and the utility of the folate-derived PET radioconjugates for targeting FR-positive tumors. For the most part, results from folate radioconjugates labeled with fluorine-18 (t1/2 = 109.8 min) and gallium-68 (t1/2 = 67.7 min) have been presented but folates labeled with “exotic” and new PET radionuclides such as copper-64 (t1/2 = 12.7 h), terbium-152 (t1/2 = 17.5 h), scandium-44 (t1/2 = 3.97 h), cobalt-55 (t1/2 = 17.5 h) and zirconium-89 (t1/2 = 78.4 h) are also discussed. For tumor imaging, none of the reported PET radiolabeled folates reported to date has made the complete bench-to-bedside journey except 18FAzaFol, which made it to patients with metastatic ovarian and lung cancers in a multicenter first-in-human trial. In the near future, however, we expect more clinical trials with folate-based PET radiopharmaceuticals given the increasing clinical interest in imaging and the treatment of FR-related malignancies.
Over the past two decades, our understanding of the endocannabinoid system has greatly improved due to the wealth of results obtained from exploratory studies. Currently, two cannabinoid receptor ...subtypes have been well-characterized. The cannabinoid receptor type 1 (CB1) is widely expressed in the central nervous system, while the levels of the cannabinoid receptor type 2 (CB2) in the brain and spinal cord of healthy individuals are relatively low. However, recent studies demonstrated a CB2 upregulation on activated microglia upon neuroinflammation, an indicator of neurodegeneration. Our research group aims to develop a suitable positron emission tomography (PET) tracer to visualize the CB2 receptor in patients suffering from neurodegenerative diseases. Herein we report two novel thiophene-based (11)C-labeled PET ligands designated (11)CAAT-015 and (11)CAAT-778. The reference compounds were synthesized using Gewald reaction conditions to obtain the aminothiophene intermediates, followed by amide formation. Saponification of the esters provided their corresponding precursors. Binding affinity studies revealed Ki-values of 3.3 ± 0.5 nM (CB2) and 1.0 ± 0.2 μM (CB1) for AAT-015. AAT-778 showed similar Ki-values of 4.3 ± 0.7 nM (CB2) and 1.1 ± 0.1 μM (CB1). Radiosynthesis was carried out under basic conditions using (11)Ciodomethane as methylating agent. After semi-preparative HPLC purification both radiolabeled compounds were obtained in 99% radiochemical purity and the radiochemical yields ranged from 12 to 37%. Specific activity was between 96 and 449 GBq/μmol for both tracers. In order to demonstrate CB2 specificity of (11)CAAT-015 and (11)CAAT-778, we carried out autoradiography studies using CB2-positive mouse/rat spleen tissues. The obtained results revealed unspecific binding in spleen tissue that was not blocked by an excess of CB2-specific ligand GW402833. For in vivo analysis, (11)CAAT-015 was administered to healthy rats via tail-vein injection. Evaluation of the CB2-positive spleen, however, showed no accumulation of the radiotracer. Despite the promising in vitro binding affinities, specific binding of (11)CAAT-015, and (11)CAAT-778 could not be demonstrated.
Background
The NMDA receptor (NMDAR) plays a key role in the central nervous system, e.g., for synaptic transmission. While synaptic NMDARs are thought to have protective characteristics, activation ...of extrasynaptic NMDARs might trigger excitotoxic processes linked to neuropsychiatric disorders. Since extrasynaptic NMDARs are typically GluN2B-enriched, the subunit is an interesting target for drug development and treatment monitoring. Recently, the novel GluN2B-specific PET radioligand
(R)
-
11
CMe-NB1 was investigated in rodents and for the first time successfully translated to humans. To assess whether
(R)
-
11
CMe-NB1 is a valuable radioligand for (repeated) clinical applications, we evaluated its safety, biodistribution and dosimetry.
Methods
Four healthy subjects (two females, two males) underwent one whole-body PET/MR measurement lasting for more than 120 min. The GluN2B-specific radioligand
(R)
-
11
CMe-NB1 was administered simultaneously with the PET start. Subjects were measured in nine passes and six bed positions from head to mid-thigh. Regions of interest was anatomically defined for the brain, thyroid, lungs, heart wall, spleen, stomach contents, pancreas, liver, kidneys, bone marrow and urinary bladder contents, using both PET and MR images. Time-integrated activity coefficients were estimated to calculate organ equivalent dose coefficients and the effective dose coefficient. Additionally, standardized uptake values (SUV) were computed to visualize the biodistribution.
Results
Administration of the radioligand was safe without adverse events. The organs with the highest uptake were the urinary bladder, spleen and pancreas. Organ equivalent dose coefficients were higher in female in almost all organs, except for the urinary bladder of male. The effective dose coefficient was 6.0 µSv/MBq.
Conclusion
The GluN2B-specific radioligand
(R)
-
11
CMe-NB1 was well-tolerated without reported side effects. Effective dose was estimated to 1.8 mSv when using 300 MBq of presented radioligand. The critical organ was the urinary bladder. Due to the low effective dose coefficient of this radioligand, longitudinal studies for drug development and treatment monitoring of neuropsychiatric disorders including neurodegenerative diseases are possible.
Trial registration
Registered on 11th of June 2019 at
https://www.basg.gv.at
(EudraCT: 2018-002933-39).
The quad-HIDAC small animal PET camera is a quadratic array of high-density avalanche chambers; the camera described in this publication consists of 16 modules. We present the system response using ...point and line sources and a mouse phantom. The quad-HIDAC camera exhibits a count rate stability of better than 1% and linearity of response to coincidences up to 2.2 x 10(5) cps at 16 MBq activity. Corrected for deadtime and random coincidences, the efficiency for the line source is 0.011, of which unscattered coincidences yield 0.009. The scatter fraction originating from the detectors is 0.22. Absorption within the mouse phantom was 20% and the scatter fraction increased to 0.29. Resolution is uniform within the entire field-of-view, which is 28 cm axially and 17 cm radially. Reconstruction of a point source yields a resolution of 1.1 mm FWHM for all three components. The performance of the camera demonstrates its excellent suitability for the functional imaging of small animals.
Background
Noninvasive preclinical imaging methodologies such as small animal positron emission tomography (PET) allow the repeated measurement of the same subject which is generally assumed to ...reduce the variability of the experimental outcome parameter and to produce more robust results. In this study, the variability of tracer uptake in the rodent brain was assessed within and between subjects using the established radiopharmaceuticals
18
F-FDG and
18
F-fallypride. Moreover, experimental factors with potential impact on study outcome were elicited, and the effect of their strict homogenization was assessed.
Methods
Brain standardized uptake values of rodents were compared between three PET scans of the same animal and scans of different individuals.
18
F-FDG
ex vivo
tissue sampling was performed under variation of the following experimental parameters: gender, age, cage occupancy, anesthetic protocol, environmental temperature during uptake phase, and tracer formulation
.
Results
No significant difference of variability in
18
F-FDG or
18
F-fallypride brain or striatal uptake was identified between scans of the same and scans of different animals (COV = 14 ± 7% vs. 21 ± 10% for
18
F-FDG).
18
F-FDG brain uptake was robust regarding a variety of experimental parameters; only anesthetic protocols showed a significant impact. In contrast to a heterogenization approach, homogenization of groups produced more false positive effects in
18
F-FDG organ distribution showing a false positive rate of 9% vs. 6%.
Conclusions
Repeated measurements of the same animal may not reduce data variability compared with measurements on different animals. Controlled heterogenization of test groups with regard to experimental parameters is advisable as it decreases the generation of false positive results and thus increases external validity of study outcome.
Hypoxia predicts poor treatment response of malignant tumors. We used PET with (18)F-fluoromisonidazole ((18)F-FMISO) and (15)O-H(2)O to measure in vivo hypoxia and perfusion in patients with brain ...tumors.
Eleven patients with various brain tumors were investigated. We performed dynamic (18)F-FMISO PET, including arterial blood sampling and the determination of (18)F-FMISO stability in plasma with high-performance liquid chromatography (HPLC). The (18)F-FMISO kinetics in normal brain and tumor were assessed quantitatively using standard 2- and 3-compartment models. Tumor perfusion ((15)O-H(2)O) was measured immediately before (18)F-FMISO PET in 10 of the 11 patients.
PET images acquired 150-170 min after injection revealed increased (18)F-FMISO tumor uptake in all glioblastomas. This increased uptake was reflected by (18)F-FMISO distribution volumes >1, compared with (18)F-FMISO distribution volumes <1 in normal brain. The (18)F-FMISO uptake rate K(1) was also higher in all glioblastomas than in normal brain. In meningioma, which lacks the blood-brain barrier (BBB), a higher K(1) was observed than in glioblastoma, whereas the (18)F-FMISO distribution volume in meningioma was <1. Pixel-by-pixel image analysis generally showed a positive correlation between (18)F-FMISO tumor uptake at 0-5 min after injection and perfusion ((15)O-H(2)O) with r values between 0.42 and 0.86, whereas late (18)F-FMISO images (150-170 min after injection) were (with a single exception) independent of perfusion. Spatial comparison of (18)F-FMISO with (15)O-H(2)O PET images in glioblastomas showed hypoxia both in hypo- and hyperperfused tumor areas. HPLC analysis showed that most of the (18)F-FMISO in plasma was still intact 90 min after injection, accounting for 92%-96% of plasma radioactivity.
Our data suggest that late (18)F-FMISO PET images provide a spatial description of hypoxia in brain tumors that is independent of BBB disruption and tumor perfusion. The distribution volume is an appropriate measure to quantify (18)F-FMISO uptake. The perfusion-hypoxia patterns described in glioblastoma suggest that hypoxia in these tumors may develop irrespective of the magnitude of perfusion.
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