Single-photon Emission Computed Tomography Tracers Research Articles

Expanding a peptide-covalent probe hybrid for PET imaging of S. aureus driven focal infections

BackgroundThe urgent demand for innovative theranostic strategies to combat bacterial resistance to antibiotics is evident, with substantial implications for global health. Rapid diagnosis of life-threatening infections can expedite treatment, improving patient outcomes. Leveraging diagnostic modalities i.e., positron emission tomography (PET) and single photon emission computed tomography (SPECT) for detecting focal infections has yielded promising results. Augmenting the sensitivity of current PET and SPECT tracers could enable effective imaging of pathogenic bacteria, including drug-resistant strains.UBI (29–41), an antimicrobial peptide (AMP) fragment recognizes the S. aureus membrane through electrostatic binding. Radiolabeled UBI (29–41) is a promising SPECT and PET-based tracer for detecting focal infections. 2-APBA (2-acetyl-phenyl-boronic acid), a non-natural amino acid, specifically targets lysyl-phosphatidyl-glycerol (lysyl-PG) on the S. aureus membranes, particularly in AMP-resistant strains. We propose that combining UBI with 2-APBA could enhance the diagnostic potential of radiolabeled UBI.ResultsPresent work aimed to compare the diagnostic potential of two radiolabeled peptides, namely UBI (29–41) and 2-APBA modified UBI (29–41), referred to as UBI and UBI-APBA. APBA modification imparted antibacterial activity to the initially non-bactericidal UBI against S. aureus by inducing a loss of membrane potential. The antibacterial activity demonstrated by UBI-APBA can be ascribed to the synergistic interaction of both UBI and UBI-APBA on the bacterial membrane. To enable PET imaging, we attached the chelator 1,4,7-triazacyclononane 1-glutaric acid 4,7-acetic acid (NODAGA) to the peptides for complexation with the positron emitter Gallium-68 (68Ga). Both NODAGA conjugates were radiolabeled with 68Ga with high radiochemical purity. The resultant 68Ga complexes were stable in phosphate-buffered saline and human serum. Uptake of these complexes was observed in S. aureus but not in mice splenocytes, indicating the selective nature of their interaction. Additionally, the APBA conjugate exhibited superior uptake in S. aureus while preserving the selectivity of the parent peptide. Furthermore, [68Ga]Ga-UBI-APBA demonstrated accumulation at the site of infection in rats, with an improved target-to-non-target ratio, as evidenced by ex-vivo biodistribution and PET imaging.ConclusionsOur findings suggest that linking UBI, as well as AMPs in general, with APBA shows promise as a strategy to augment the theranostic potential of these molecules.

Ictal Single Photon Emission Computed Tomography (SPECT) In Patients with Focal Aware Seizure without Ictal Electroencephalographic Changes: A Single Center Experience (P2-1.012)

<h3>Objective:</h3> N/A <h3>Background:</h3> There is currently limited literature on the localization value of ictal SPECT tracer injection during patient-reported typical focal aware seizures (auras) that lack electrographic changes. One study reported that ictal SPECT studies in isolated auras lack reliability, with concordant localization with the seizure onset zone obtained in 5%, and lateralization in 35% of cases. In another study, localizing information of self-injection of ictal SPECT was better in three patients and obviated the need for intracranial monitoring in one patient. We present a study in which tracer injection was administered for patient-reported typical focal aware seizures, where the subsequent analysis of ictal and interictal SPECT helped inform further management. <h3>Design/Methods:</h3> We performed a retrospective review of cases who underwent ictal SPECT between 2020 to 2022 at University of Kentucky hospital. Cases with radiotracer injection during patient-reported auras lacking electrographic changes were identified. Timing of injection from onset of reported aura, hyperperfusion changes on ictal SPECT, and the outcome of imaging on further management of refractory epilepsy were noted. <h3>Results:</h3> 20 patients underwent ictal SPECT, of which 7 met our inclusion criteria. None of the 7 cases had electrographic correlate with aura on scalp EEG. Time of tracer injection ranged from 1–17 seconds following onset of aura. The ictal SPECT changes correctly localized the seizure onset zone in five patients. This was followed by intracranial monitoring and subsequent temporal lobectomy in three patients, interventricular ablation of epileptogenic focus in one patient, and Responsive Neurostimulation implant in one patient. One patient was managed medically, and one is ongoing pre-surgical evaluation. <h3>Conclusions:</h3> Ictal SPECT with radiotracer injection during typical focal aware seizures (patient reported auras) without ictal electrographic changes is helpful in the localization of the seizure onset zone. Additional studies with larger sample size and outcome information are needed to assess accuracy of localization. <b>Disclosure:</b> Dr. Pervin has nothing to disclose. Dr. Khan has received personal compensation for serving as an employee of University of Kentucky. Dr. Clay has nothing to disclose. Riham El Khouli has nothing to disclose. Dr. Mirza has nothing to disclose. Dr. Mathias has received research support from My Epilepsy Society Non Profit Organization.

Different hemodynamics of basal ganglia between moyamoya and non-moyamoya diseases using intravoxel incoherent motion imaging and single-photon emission computed tomography.

Moyamoya disease (MMD) and non-MMD have different pathogenesis, clinical presentation, and treatment policy. To identify differences in hemodynamics between MMD and non-MMD using intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT). Patients who had undergone 99mTc-ECD or 123I-IMP SPECT, and IVIM imaging were retrospectively studied. IVIM imaging was acquired using six different b-values. Cerebral blood flow ratio (CBFR) in the basal ganglia was calculated using a standardized volume-of-interest template. The cerebellum was used as a reference region. IVIM perfusion fraction (f) was obtained using a two-step fitting algorithm. Elliptical regions of interest were placed in bilateral basal ganglia on the IVIM f map. Patients were classified into MMD and non-MMD groups. The correlation between CBFR and mean IVIM f (fmean) in the basal ganglia was evaluated using Spearman's rank correlation coefficient. In total, 20 patients with MMD and 28 non-MMD patients were analyzed. No significant differences in fmean were observed among MMD, affected hemisphere with non-MMD (non-MMDaff), and unaffected hemispheres with non-MMD (non-MMDunaff). A negative correlation was seen between fmean and CBFR in the MMD group (r = -0.40, P = 0.0108), but not in the non-MMD group (non-MMDaff, r = 0.07, P = 0.69; non-MMDunaff, r = -0.22, P = 0.29). No significant differences were found among MMD and non-MMD patients, irrespective of SPECT tracers. The combination of IVIM MRI and SPECT appears to allow non-invasive identification of differences in hemodynamics between MMD and non-MMD.

Simultaneous in vivo imaging with PET and SPECT tracers using a Compton-PET hybrid camera

Positron-emission tomography (PET) and single-photon-emission computed tomography (SPECT) are well-established nuclear-medicine imaging methods used in modern medical diagnoses. Combining PET with 18F-fluorodeoxyglucose (FDG) and SPECT with an 111In-labelled ligand provides clinicians with information about the aggressiveness and specific types of tumors. However, it is difficult to integrate a SPECT system with a PET system because SPECT requires a collimator. Herein, we describe a novel method that provides simultaneous imaging with PET and SPECT nuclides by combining PET imaging and Compton imaging. The latter is an imaging method that utilizes Compton scattering to visualize gamma rays over a wide range of energies without requiring a collimator. Using Compton imaging with SPECT nuclides, instead of the conventional SPECT imaging method, enables PET imaging and Compton imaging to be performed with one system. In this research, we have demonstrated simultaneous in vivo imaging of a tumor-bearing mouse injected with 18F-FDG and an 111In-antibody by using a prototype Compton-PET hybrid camera. We have succeeded in visualizing accumulations of 18F-FDG and 111In-antibody by performing PET imaging and Compton imaging simultaneously. As simultaneous imaging utilizes the same coordinate axes, it is expected to improve the accuracy of diagnoses.

Synthesis and evaluation of N-isopropyl-p-[11C]methylamphetamine as a novel cerebral blood flow tracer for positron emission tomography

IntroductionIncreases in fasting plasma glucose (PG) levels lead to a decrease in 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) uptake in the normal brain, especially in the precuneus, resulting in an Alzheimer’s disease (AD)-like uptake pattern. Therefore, patients with higher PG levels, such as those with diabetes, can be erroneously diagnosed with AD when positron emission tomography (PET) imaging is done using [18F]FDG, due to reduced uptake of [18F]FDG in the precuneus. To help avoid an erroneous diagnosis of AD due to differences in glucose metabolism, evaluating cerebral blood flow (CBF) in the brain is useful. However, current techniques such as single photon emission computed tomography (SPECT) and [15O]H2O PET have limitations regarding early diagnosis of AD because the images they produce are of low resolution. Here, we developed a novel CBF PET tracer that may be more useful than [18F]FDG for diagnosis of AD.MethodsWe synthesized and evaluated N-isopropyl-p-[11C]methylamphetamine ([11C]4) as a carbon-11-labeled analogue of the standard CBF SPECT tracer N-isopropyl-p-[123I]iodoamphetamine. Fundamental biological evaluations such as biodistribution, peripheral metabolism in mice, and brain kinetics of [11C]4 in non-human primates with PET with successive measurement of [15O]H2O were performed.Results[11C]4 was synthesized by methylation of the corresponding tributyltin precursor (2) with [11C]MeI in a palladium-promoted Stille cross-coupling reaction. The brain uptake of [11C]4 in mice peaked at 5–15 min after injection and then promptly decreased. Most radioactivity in the brain was detected in the unchanged form, although in the periphery, [11C]4 was rapidly metabolized to hydrophilic components. Acetazolamide (AZM) treatment significantly increased the brain uptake of [11C]4 without affecting the blood levels of radioactivity in mice. Preliminary kinetics analysis showed that the K1 of [11C]4 reflected regional CBF in a vehicle-treated monkey, but that the K1 did not reflect CBF in higher flow regions after AZM loading.Conclusion[11C]4 is a potential novel CBF PET tracer. Further validation studies are needed before [11C]4 can be used in humans.

Improved Noninvasive In Vivo Tracking of AAV-9 Gene Therapy Using the Perchlorate-Resistant Sodium Iodide Symporter from Minke Whale

The sodium iodide symporter (NIS) is widely used as a reporter gene to noninvasively monitor the biodistribution and durability of vector-mediated gene expression via gamma scintigraphy, single-photon emission computed tomography (SPECT), and positron-emission tomography (PET). However, the approach is limited by background signal due to radiotracer uptake by endogenous NIS-expressing tissues. In this study, using the SPECT tracer pertechnetate (99mTcO4) and the PET tracer tetrafluoroborate (B18F4), in combination with the NIS inhibitor perchlorate, we compared the transport properties of human NIS and minke whale (Balaenoptera acutorostrata scammoni) NIS in vitro and in vivo. Based on its relative resistance to perchlorate, the NIS protein from minke whale appeared to be the superior candidate reporter gene. SPECT and PET imaging studies in nude mice challenged with NIS-encoding adeno-associated virus (AAV)-9 vectors confirmed that minke whale NIS, in contrast to human and endogenous mouse NIS, continues to function as a reliable reporter even when background radiotracer uptake by endogenous NIS is blocked by perchlorate.

Feasibility studies of radioiodinated pyridyl benzofuran derivatives as potential SPECT imaging agents for prion deposits in the brain

IntroductionPrion diseases are fatal neurodegenerative disorders caused by the deposition of abnormal prion protein aggregates (PrPSc) in the central nervous system. This study aimed to evaluate the use of iodinated pyridyl benzofuran (IPBF) derivatives as single-photon emission computed tomography (SPECT) probes for the detection of cerebral PrPSc deposits. MethodsIn vitro binding assays of IPBF derivatives were carried out in the recombinant mouse prion protein (rMoPrP) and brain sections of mouse-adapted bovine spongiform encephalopathy (mBSE)-infected mice. SPECT imaging of 5-(5-[123I]iodobenzofuran-2-yl)-N-methylpyridin-2-amine ([123I]IPBF-NHMe) was performed on mBSE-infected and mock-infected mice. ResultsFluorescence microscopy results showed that fluorescence signals of IPBF derivatives corresponded to the thioflavin-T positive amyloid deposits of PrPSc in the brain sections of mouse-adapted bovine spongiform encephalopathy (mBSE)-infected mice. Among the IPBF derivatives, 5-(5-iodobenzofuran-2-yl)-N-methylpyridin-2-amine (IPBF-NHMe) exhibited the highest binding affinity to the recombinant mouse prion protein (rMoPrP) aggregates with a Ki of 14.3 nM. SPECT/computed tomography (CT) imaging and ex vivo autoradiography demonstrated that the [123I]IPBF-NHMe distribution in brain tissues of mBSE-infected mice co-localized with PrPSc deposits. Conclusion[123I]IPBF-NHMe appears to be a prospective SPECT tracer for monitoring prion deposits in living brain tissues.

PET and SPECT imaging of the brain: a review on the current status of nuclear medicine in Japan.

Radiolabeled tracers allow visualization of not only perfusion, but receptors, function, and metabolism as well. Although spatial resolution is lower than that of computed tomography and magnetic resonance imaging, positron emission tomography (PET) and single photon emission computed tomography (SPECT) have great potential for target-specific imaging. In this review, we discuss several SPECT and PET tracers used in brain imaging, specifically focusing on tracers currently available, or developed, in Japan. Several important and sophisticated methods exist for analysis of brain PET and SPECT images. Two of them, quantitative cerebral blood flow measurement and voxel-based statistical analysis are discussed in this review. The former method, which employs acetazolamide loading, is useful for evaluation of the brain perfusion reserve for ischemic brain diseases. The latter is useful in diagnosing dementing diseases. Additionally, great strides have been made in the development of the technology used in the scanners. New SPECT systems based on cadmium-zinc-telluride, PET/MRI, and semiconductor PET/CT may provide higher spatial resolution with an acquisition time shorter than ever before. Such developments of both tracers and scanners can be integrated for unprecedented imagery of the brain, providing valuable insight into underlying causes of some fatal brain disorders.

Single Photon Emission Computed Tomography Tracer.

Single photon emission computed tomography (SPECT) is the state-of-the-art imaging modality in nuclear medicine despite the fact that only a few new SPECT tracers have become available in the past 20years. Critical for the future success of SPECT is the design of new and specific tracers for the detection, localization, and staging of a disease and for monitoring therapy. The utility of SPECT imaging to address oncologic questions is dependent on radiotracers that ideally exhibit excellent tissue penetration, high affinity to the tumor-associated target structure, specific uptake and retention in the malignant lesions, and rapid clearance from non-targeted tissues and organs. In general, a target-specific SPECT radiopharmaceutical can be divided into two main parts: a targeting biomolecule (e.g., peptide, antibody fragment) and a γ-radiation-emitting radionuclide (e.g., 99mTc, 123I). If radiometals are used as the radiation source, a bifunctional chelator is needed to link the radioisotope to the targeting entity. In a rational SPECT tracer design, these single components have to be critically evaluated in order to achieve a balance among the demands for adequate target binding, and a rapid clearance of the radiotracer. The focus of this chapter is to depict recent developments of tumor-targeted SPECT radiotracers for imaging of cancer diseases. Possibilities for optimization of tracer design and potential causes for design failure are discussed and highlighted with selected examples.

Double Photon Emission Coincidence Imaging using GAGG-SiPM pixel detectors

Single photon emission computed tomography(SPECT) is a useful medical imaging modality using single photon detection from radioactive tracers, such as 99Tc and 111In, however further development of increasing the contrast in the image is still under investigation. A novel method (Double Photon Emission CT / DPECT) using a coincidence detection of two cascade gamma-rays from 111In is proposed and characterized in this study. 111In, which is well-known and commonly used as a SPECT tracer, emits two cascade photons of 171 keV and 245 keV with a short delay of approximately 85 ns. The coincidence detection of two gamma-rays theoretically determines the position in a single point compared with a line in single photon detection and increases the signal to noise ratio drastically. A fabricated pixel detector for this purpose consists of 8 × 8 array of high-resolution type 1.5 mm thickness Ce:GAGG (3.9% @ 662 keV, 6.63g/cm3, C&A Co. Ce:Gd3Ga2.7Al2.3O12 2.5 × 2.5 × 1.5 mm3) crystals coupled a 3 mm pixel SiPM array (Hamamatsu MPPC S13361-2050NS-08). The signal from each pixel is processed and readout using time over threshold (TOT) based parallel processing circuit to extract the energy and timing information. The coincidence was detected by FPGA with the frequency of 400 MHz. Two pixel detectors coupled to parallel-hole collimators are located at the degree of 90 to determine the position and coincidence events (time window =1 μs) are detected and used for making back-projection image. The basic principle of DPECT is characterized including the detection efficiency and timing resolution.

Novel Radiolabeled Bisphosphonates for PET Diagnosis and Endoradiotherapy of Bone Metastases.

Bone metastases, often a consequence of breast, prostate, and lung carcinomas, are characterized by an increased bone turnover, which can be visualized by positron emission tomography (PET), as well as single-photon emission computed tomography (SPECT). Bisphosphonate complexes of 99mTc are predominantly used as SPECT tracers. In contrast to SPECT, PET offers a higher spatial resolution and, owing to the 68Ge/68Ga generator, an analog to the established 99mTc generator exists. Complexation of Ga(III) requires the use of chelators. Therefore, DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), NOTA (1,4,7-triazacyclododecane-1,4,7-triacetic acid), and their derivatives, are often used. The combination of these macrocyclic chelators and bisphosphonates is currently studied worldwide. The use of DOTA offers the possibility of a therapeutic application by complexing the β-emitter 177Lu. This overview describes the possibility of diagnosing bone metastases using [68Ga]Ga-BPAMD (68Ga-labeled (4-{[bis-(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid) as well as the successful application of [177Lu]Lu-BPAMD for therapy and the development of new diagnostic and therapeutic tools based on this structure. Improvements concerning both the chelator and the bisphosphonate structure are illustrated providing new 68Ga- and 177Lu-labeled bisphosphonates offering improved pharmacological properties.

99mTc-Tetrofosmin Uptake Correlates with the Sensitivity of Glioblastoma Cell Lines to Temozolomide.

99mTc-tetrofosmin (99mTc-TF) is a single-photon emission computed tomography tracer that has been used for brain tumor imaging. The aim of the study was to assess if 99mTc-TF uptake by glioblastoma cells correlates with their response to temozolomide (TMZ). We investigated the correlation of TMZ antitumor effect with the 99mTc-TF uptake in two glioblastoma cell lines. The U251MG cell line is sensitive to TMZ, whereas T98G is resistant. Viability and proliferation of the cells were examined by trypan blue exclusion assay and xCELLigence system. Cell cycle was analyzed with flow cytometry. The radioactivity in the cellular lysate was measured with a gamma scintillation counter. TMZ induced G2/M cell cycle arrest in U251MG cells, whereas there was no effect on cell cycle in T98G cells. Lower 99mTc-TF uptake was observed in U251MG cells that were exposed to TMZ compared to control (P = 0.0159). No significant difference in respect to 99mTc-TF uptake was found in T98G cells when exposed to TMZ compared to control (P = 0.8). With 99mTc-TF, it was possible to distinguish between TMZ-sensitive and resistant glioblastoma cells within 6 h of treatment initiation. Thus, 99mTc-TF uptake may consist a novel approach to assess an early response of glioblastoma to chemotherapy and deserves further investigation.

Molecular Imaging of Hydrolytic Enzymes Using PET and SPECT.

Hydrolytic enzymes are a large class of biological catalysts that play a vital role in a plethora of critical biochemical processes required to maintain human health. However, the expression and/or activity of these important enzymes can change in many different diseases and therefore represent exciting targets for the development of positron emission tomography (PET) and single-photon emission computed tomography (SPECT) radiotracers. This review focuses on recently reported radiolabeled substrates, reversible inhibitors, and irreversible inhibitors investigated as PET and SPECT tracers for imaging hydrolytic enzymes. By learning from the most successful examples of tracer development for hydrolytic enzymes, it appears that an early focus on careful enzyme kinetics and cell-based studies are key factors for identifying potentially useful new molecular imaging agents.

Nanoparticles and radiotracers: advances toward radionanomedicine.

In this study, we cover the convergence of radiochemistry for imaging and therapy with advances in nanoparticle (NP) design for biomedical applications. We first explore NP properties relevant for therapy and theranostics and emphasize the need for biocompatibility. We then explore radionuclide-imaging modalities such as positron emission tomography (PET), single-photon emission computed tomography (SPECT), and Cerenkov luminescence (CL) with examples utilizing radiolabeled NP for imaging. PET and SPECT have served as diagnostic workhorses in the clinic, while preclinical NP design examples of multimodal imaging with radiotracers show promise in imaging and therapy. CL expands the types of radionuclides beyond PET and SPECT tracers to include high-energy electrons (β- ) for imaging purposes. These advances in radionanomedicine will be discussed, showing the potential for radiolabeled NPs as theranostic agents. WIREs Nanomed Nanobiotechnol 2016, 8:872-890. doi: 10.1002/wnan.1402 For further resources related to this article, please visit the WIREs website.

The antagonist SPECT tracer 123I-iododexetimide binds preferentially to the muscarinic M1 receptor in-vivo, but is it also a potential tool to assess the occupancy of muscarinic M1 receptors by agonists?

Cognitive deterioration in neuropsychiatric disorders is associated with high attrition rates giving an urgent need to develop better pharmaceutical therapies. The underlying mechanisms of cognitive impairments are unclear but research has shown that the muscarinic receptor subtype 1 (M 1 receptor ) plays a critical role. Blocking the M 1 receptor gives rise to profound cognitive deficits, while the administration of M 1 agonist drugs improves cognitive functioning. In this research highlight we will outline supporting data that the radiotracer 123 I-iododexetimide preferentially binds to the M 1 receptor in-vivo and can be used to assess changes in M 1 receptor expression in-vivo associated with cognitive decline. These findings come from a previously published paper extensively examining binding characteristics of 123/127 I-iododexetimide to muscarinic receptors. Results of biodistribution studies also has shown that acute administration of the M 1 / 4 receptor agonist xanomeline could inhibit 127 I-iododexetimide binding in M 1 -rich brain areas in rats, suggesting that 123 I-iododexetimide may also be used to evaluate the occupancy of M 1 receptors by M 1 agonists in-vivo. This may be of clinical relevance considering the efficacy of M 1 agonist drugs in the treatment of cognitive deficits. Here we show the results from new biodistribution experiments in rats conducted to test the hypothesis that 123 I-iododexetimide may be a useful radiotracer to evaluate the M 1 receptor occupancy by M 1 agonists in-vivo. Contrary to our expectations, no significant change in 123 I-iododexetimide ex-vivo binding was observed after acute administration of xanomeline in M 1 receptor-rich brain areas, whereas significantly decreased 123 I-iododexetimide binding was found after chronic treatment with xanomeline. 123 I-iododexetimide single photon emission computed tomography (SPECT) may therefore be a useful imaging tool to further evaluate M 1 receptor changes in neuropsychiatric disorders, as a potential stratifying biomarker, to assess the occupancy of M 1 receptors after M 1 antagonist treatment, or after chronic treatment with M 1 agonists, although it may be less suited to evaluate the M 1 receptor occupancy after acute treatment with M 1 agonists. Future studies should concentrate efforts towards finding also an M 1 agonist radiotracer for positron emission tomography (PET) or SPECT to assess the working mechanism of M 1 agonists.

Imaging of human pancreatic cancer xenografts by single-photon emission computed tomography with 99mTc-Hynic-PEG-AE105.

The elevated expression of urokinase-type plasminogen activator receptor (uPAR) is associated with the poor prognosis of pancreatic cancer patients. Thus, uPAR is a promising candidate as a molecular target for the non-invasive imaging of pancreatic cancer. The present study aimed to develop a technetium-99m (99mTc)-labeled uPAR-binding peptide for non-invasive single-photon emission computed tomography (SPECT) assessment of uPAR expression in pancreatic cancer xenograft models. A linear high-affinity uPAR peptide antagonist, Hynic-PEG-AE105, was labeled with 99mTc. Human uPAR-positive pancreatic cancer BxPC-3 cells were inoculated into nude mice. SPECT was performed in the pancreatic cancer xenograft mice models. The results showed that the rate of the 99mTc labeling of Hynic-PEG-AE105 was 97.72±1.73%. The tumor uptake of 99mTc-Hynic-PEG-AE105 was higher than the control inactive peptide 99mTc-Hynic-PEG-AE105mut at 4 h (3.37±0.11 vs. 1.36±0.18; P<0.001) and 6 h (3.64±0.25 vs. 1.28±0.20; P<0.001) (n=10). Moreover, a significant correlation was observed between the tumor uptake of 99mTc-Hynic-PEG-AE105 and uPAR expression (r=0.791, P=0.006). In conclusion, in the present study, a peptide-based SPECT tracer, 99mTc-Hynic-PEG-AE105, with a high purity and specific radioactivity was synthesized. 99mTc-Hynic-PEG-AE105 is a promising agent for the non-invasive determination of uPAR expression in pancreatic cancer.

MS565: A SPECT Tracer for Evaluating the Brain Penetration of BAF312 (Siponimod).

BAF312 (siponimod) is a sphingosine-1-phosphate (S1P) receptor modulator in clinical development for the treatment of multiple sclerosis, with faster organ/tissue distribution and elimination kinetics than its precursor FTY720 (fingolimod). Our aim was to develop a tracer to better quantify the penetration of BAF312 in the human brain, with the potential to be labeled for positron emission tomography (PET) or single-photon emission computed tomography (SPECT). Although the PET radioisotopes (11)C and (18)F could have been introduced in BAF312 without modifying its structure, they do not have decay kinetics compatible with the time required for observing the drug's organ distribution in patients. In contrast, the SPECT radioisotope (123) I has a longer half-life and would suit this purpose. Herein we report the identification of an iodinated derivative of BAF312, (E)-1-(4-(1-(((4-cyclohexyl-3-iodobenzyl)oxy)imino)ethyl)-2-ethylbenzyl)azetidine-3-carboxylic acid (18, MS565), as a SPECT tracer candidate with affinity, S1P receptor selectivity, overall physicochemical properties, and blood pharmacokinetics similar to those of the original molecule. A whole-body autoradiography study performed with [(14)C]MS565 subsequently confirmed that its organ distribution is similar to that of BAF312. This validates the selection of MS565 for (123)I radiolabeling and for use in imaging studies to quantify the brain penetration of BAF312.

Advances in CNS Imaging Agents: Focus on PET and SPECT Tracers in Experimental and Clinical Use.

The physiological functioning of the brain is not well-known in current day medicine and the pathologies of many neuropsychiatric disorders are still not yet fully understood. With our aging population and better life expectancies, it has become imperative to find better biomarkers for disease progression as well as receptor target engagements. In the last decade, these major advances in the field of molecular CNS imaging have been made available with tools such as functional magnetic resonance imaging (fMRI), magnetic resonance spectroscopy (MRS), single photon emission computed tomography (SPECT), and neuroreceptor-targeted positron emission tomography (PET). These tools have given researchers, pharmaceutical companies, and clinical physicians a better method of understanding CNS dysfunctions, and the ability to employ improved therapeutic agents. This review is intended to provide an update on brain imaging agents that are currently used in clinical and translational research toward treatment of CNS disorders. The review begins with amyloid and tau imaging, the former of which has at least three [(18)F] agents that have been recently approved and will soon be available for clinical use for specific indications in the USA and elsewhere. Other prevalent PET and SPECT neurotransmitter system agents, including those newly US FDA-approved imaging agents related to the dopaminergic system, are included. A review of both mature and potentially growing PET imaging agents, including those targeting serotonin and opiate receptor systems, is also provided.

Utility of 99mTc-PEG4-E[PEG4-c(RGDfK)]2 in Posttherapy Surveillance of Patients with Reelevated Carcinoembryonic Antigen Levels

Objectives: To evaluate the efficacy of ^99mTc-PEG₄-E[PEG₄-c (RGDfK)]₂ (^99mTc-3PRGD2) single photon emission computed tomography (SPECT) in monitoring the recurrence of malignancies. Materials and Methods:^99mTc-3PRGD2 SPECT was performed on 28 patients (10 females and 18 males; median age 49.2 years) suspected of recurrent malignancies due to an asymptomatically reelevated carcinoembryonic antigen level. The SPECT was performed 0.5 h after an intravenous injection of 11.1 MBq/kg (0.3 mCi/kg) of ^99mTc-3PRGD2. The SPECT and concurrent contrast-enhanced computed tomography (ceCT) findings were analyzed with reference to the histopathological findings and/or clinical follow-up data. Results: Recurrences were identified in 20 out of the 28 patients (prevalence 71.4%) with altogether 26 lesions. Fifteen lesions were confirmed by histopathological findings, and the other 11 lesions were confirmed by serial radiological or clinical follow-up. Of the 20 patients with recurrent malignancies, 12 (60%) were correctly identified by ^99mTc-3PRGD2 SPECT. In the patient-based analysis, the sensitivity and specificity of ^99mTc-3PRGD2 SPECT were 60 and 100%, respectively, and the positive and negative predictive values were 100 and 50%, respectively. In the lesion-based evaluation, the sensitivity and specificity were 62 and 100%, respectively. The sensitivity and specificity of the ceCT in the patient-based evaluation were 60 and 75%, respectively, and the positive and negative predictive values were 86 and 40%, respectively. In the lesion-based evaluation, the sensitivity and specificity of the ceCT were 70 and 84%, respectively. Conclusions:^99mTc-3PRGD2, as a new SPECT tracer targeting the integrin α_vβ₃ receptor, was more useful in distinguishing recurrences as compared to ceCT.

Single-Photon Emission Computed Tomography Tracers for Predicting and Monitoring Cancer Therapy

Cancer is a lethal disease, and its therapy should be tailed to individual patients by functional imaging to optimize therapy strategies. Single-photon emission computed tomography (SPECT) is a quantitative functional imaging modality used by oncologists to monitor tumor response. SPECT can track therapy-induced biological and metabolic changes in tumors; such changes usually precede anatomical alterations. Assessment of treatment response using SPECT tracers may result in modifications in treatment planning and predicting the long-term outcome. These SPECT tracers can be classified into metabolism, cell surface receptor, intracellular receptor, microenvironment, and apoptosis tracers. The most widely used SPECT tracers include 201Tl-thallium chloride, 67Ga-gallium citrate, 123I/131I-sodium iodide, 99mTc-MIBI, 99mTc-MDP, and 123I/131I -MIBG. Apoptosis tracers, which can directly monitor early tumor response in cancer patients and can predict the outcome, have attracted increasing attention in the field of oncology. Annexin V-based SPECT tracers, including 99mTc-BTAP-annexin V, 99mTc-HYNIC-annexin-V, 99mTc-EC-annexin-V, 99mTc-i-annexin V, and 123I-annexin V, have been evaluated in clinical trials. Novel SPECT tracers, such as radiolabeled small molecules, aptamers, peptides, and proteins, need to be explored in the future to further improve the outcome of cancer therapy. In this review, SPECT tracers used to predict and monitor cancer therapy in both preclinical and clinical settings are summarized. Some tracers may contribute to the improvement of cancer therapy management.