SPECT Tracers Research Articles

EANM perspective on clinical PET and SPECT imaging in schizophrenia-spectrum disorders: a systematic review of longitudinal studies.

There is a need for biomarkers in psychiatry to improve diagnosis, prognosis and management, and with confirmed value in follow-up care. Radionuclide imaging, given its molecular imaging characteristics, is well-positioned for translation to the clinic. This systematic review lays the groundwork for integrating PET and SPECT imaging in the clinical management of schizophrenia-spectrum disorders. Systematic search of PubMed, Embase, Web of Science and Cochrane library databases was conducted from the earliest date available until February 2024. The focus was on longitudinal studies evaluating PET or SPECT imaging in individuals with a schizophrenia-spectrum or another psychotic disorders. Quality assessment was done using the Newcastle-Ottawa Scale (NOS), NIH scale for before-after studies and Cochrane Risk of Bias tool version 2 (Cochrane RoB2). Studies were further categorised into three groups: preclinical and diagnosis, predicting disease course or personalising treatment. Fifty-six studies were included in the systematic review investigating in total 1329 patients over a median of 3 months. Over two-thirds used PET tracers, whereas the remaining studies employed SPECT tracers. The most frequently investigated system was dopaminergic transmission, followed by cerebral metabolism and blood flow. [18F]FDOPA demonstrated large effect size in predicting conversion of subjects at risk and treatment response. Additionally, treatment dosage could be optimised to reduce side effects using [123I]IBZM or [11C]raclopride. Molecular imaging holds significant promise for real-life application in schizophrenia, with two particularly encouraging avenues being the prediction of conversion/response to antipsychotic medication and the improved management of antipsychotic dosage. Further longitudinal studies and clinical trials will be essential for validating both the clinical effectiveness and economic sustainability, as well as for exploring new applications.

Radiotracers for Imaging of Inflammatory Biomarkers TSPO and COX-2 in the Brain and in the Periphery.

Inflammation involves the activation of innate immune cells and is believed to play an important role in the development and progression of both infectious and non-infectious diseases such as neurodegeneration, autoimmune diseases, pulmonary and cancer. Inflammation in the brain is marked by the upregulation of translocator protein (TSPO) in microglia. High TSPO levels are also found, for example, in macrophages in cases of rheumatoid arthritis and in malignant tumor cells compared to their relatively low physiological expression. The same applies for cyclooxgenase-2 (COX-2), which is constitutively expressed in the kidney, brain, thymus and gastrointestinal tract, but induced in microglia, macrophages and synoviocytes during inflammation. This puts TSPO and COX-2 in the spotlight as important targets for the diagnosis of inflammation. Imaging modalities, such as positron emission tomography and single-photon emission tomography, can be used to localize inflammatory processes and to track their progression over time. They could also enable the monitoring of the efficacy of therapy and predict its outcome. This review focuses on the current development of PET and SPECT tracers, not only for the detection of neuroinflammation, but also for emerging diagnostic measures in infectious and other non-infectious diseases such as rheumatic arthritis, cancer, cardiac inflammation and in lung diseases.

Abstract A068: Site-specific modification of nanobodies for ImmunoPET of Liver Cancer utilizing Self-labeling nanobody-tag pair (SLANT) technology

Abstract Visualization of tumor cells is critical in diagnosing, monitoring, and treating patients with cancer. Liver cancer has an 18 percent 5-year survival rate and is the third leading cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC), the most common type of liver cancer, only takes up 18F-fluorodeoxyglucose (18F-FDG), the most commonly used clinical positron emission tomography (PET) tracer, 50% of the time. As such, developing an HCC-selective imaging agent could improve our ability for earlier diagnosis, post-treatment surveillance, and ability to increase patient longevity and quality of life. Single domain antibodies (sdAbs), or nanobodies (Nb), are attractive scaffolds for radiopharmaceutical development because of their high target affinity and specificity, ready availability from recombinant expression in bacteria, and small size for rapid clearance, better tumor penetration, and same-day imaging. However, conventional conjugation chemistry that exploits cysteines or lysines found on the native protein can abrogate the binding site of the smaller Nbs. We have previously used sortase A-based site-specific conjugation to address these challenges; however, improvements were still possible. Here, we developed a novel self-labeling Nb-tag pair (SLANT) that allows fast and specific covalent labeling of a Nb based on peptide epitope binding. We used SLANT to engineer a heterodimeric Nb construct consisting of a Nb (HN3) specific for Glypican-3, a heparin sulfate proteoglycan that is overexpressed in 75-90% of all HCCs and our self-labeling Nb. This design allows for site-specific labeling of the heterodimeric (GPC3-specific) construct in a manner that avoids modification of the tumor antigen-specific protomer. Labeling is achieved via exposure of the fusion protein to a crosslinking peptide functionalized with a chelator (DOTA). This methodology produces labeled protein at over 90 percent yields within minutes compared to less than 30 percent yields utilizing enzymatic methods. Biolayer interferometry and radioligand saturation studies were done to determine the binding affinity of the conjugate for GPC3 pre- and post-Indium-111 labeling. SPECT/CT and biodistribution studies were done at 1h, 3hrs, and 24hrs with HepG2 and HepG2-GPC3- xenografts to assess conjugate specificity and ability to accumulate in GPC3+ liver tumors. Our conjugate exhibited a nanomolar affinity for GPC3 in vitro (17-36 nM). SPECT/CT and biodistribution studies showed specificity for GPC3 in HepG2 liver cancer xenografts (~5.5% IA/g at 1-hour post-injection (p.i.)) and minimal uptake in HepG2 GPC3- tumors (~0.62% IA/g at 1-hour p.i.). Our results highlight the development of a new labeling paradigm applied to GPC3+ liver cancer. This approach can be used for same-day imaging and the rapid development of SPECT and PET imaging tracers for different cellular markers on cancer cells, addressing known tumor heterogeneity. Citation Format: Stanley Fayn, Chino C Cabalteja, Woonghee Lee, Divya Nambiar, Kwamena E Baidoo, Freddy E Escorcia, Ross W Cheloha. Site-specific modification of nanobodies for ImmunoPET of Liver Cancer utilizing Self-labeling nanobody-tag pair (SLANT) technology [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A068.

P-176 - Effects of linker and binding motif modifications on tumor uptake and distribution of 99mTc-labeled HYNIC-based PSMA-targeting SPECT tracers

P-176 - Effects of linker and binding motif modifications on tumor uptake and distribution of 99mTc-labeled HYNIC-based PSMA-targeting SPECT tracers

Head-to-Head Comparison between Peptide-Based Radiopharmaceutical for PET and SPECT in the Evaluation of Neuroendocrine Tumors: A Systematic Review

We compared head-to-head the most used radiolabeled peptides for single photon computed emission tomography (SPECT) and positron emission tomography (PET) imaging of neuroendocrine tumors (NETs). A comprehensive literature search was performed in PubMed, Web of Science, and Scopus databases. The following words, coupled two by two, were used: 68Ga-DOTATOC; 68Ga-DOTATATE; 68Ga-DOTANOC; 99mTc-EDDA/HYNIC-TOC; 64Cu-DOTATATE; and 111In-DTPA-octreotide. Moreover, a second-step search strategy was adopted by using the following combined terms: "Somatostatin receptor imaging,"; "Somatostatin receptor imaging" and "Functional,"; "Somatostatin receptor imaging" and "SPECT,"; and "Somatostatin receptor imaging" and "PET". Eligible criteria were: (1) original articles focusing on the clinical application of the radiopharmaceutical agents in NETs; (2) original articles in the English language; (3) comparative studies (head-to-head comparative or matched-paired studies). Editorials, letters to the editor, reviews, pictorial essays, clinical cases, or opinions were excluded. A total of 1077 articles were found in the three electronic databases. The full texts of 104 articles were assessed for eligibility. Nineteen articles were finally included. Most articles focused on the comparison between 111In-DTPA-Octreotide and 68Ga-DOTATOC/TATE. Few papers compared 64Cu-DOTATATE and 68Ga-DOTATOC/TATE, or SPECT tracers. The rates of true positivity were 63.7%, 58.5%, 78.4% and 82.4%, respectively, for 111In-DTPA-Octreotide, 99mTc-EDDA/HYNIC-TOC, 68Ga-DOTATATE/TOC and 64Cu-DOTATATE. In conclusion, as highly expected, PET tracers are more suitable for the in vivo identification of NETs. Indeed, in comparative studies, they demonstrated a higher true positive rate than SPECT agents.

Prostate-specific membrane antigen-directed imaging and radioguided surgery with single-photon emission computed tomography: state of the art and future outlook

ABSTRACT Introduction Prostate-specific membrane antigen (PSMA) has emerged as a highly relevant target for prostate cancer (PC) diagnosis and therapy. PSMA inhibitors targeting PSMA-enzymatic domain have been successfully labeled with radionuclides emitting positrons or gamma-photons, thus obtaining tracers suitable for imaging with positron emission computed tomography (PET/CT) or single-photon emission tomography (SPECT). Areas covered The different approaches for obtaining PSMA-ligands labeled with gamma-emitting nuclides (99mTc or111In) are reviewed. Furthermore, the applications of 99mTc/111In-PSMA SPECT for the imaging of PC patients in different clinical settings (staging or biochemical recurrence) are covered. Lastly, the employment of PSMA-targeted SPECT tracers for radioguided surgery (RGS) during primary or salvage lymphadenectomy is discussed. Expert opinion RGS provided satisfying preliminary results in both primary and salvage lymphadenectomy, allowing to discriminate between pathological and non-pathological nodes with high accuracy, although prospective studies with larger cohorts are needed to further validate this surgical approach. The potential of PSMA-targeted SPECT/CT has not been fully explored yet, but it might represent a relatively cost-effective alternative to PSMA PET/CT in limited resource environments. In this perspective, the implementation of novel SPECT technologies or algorithms, such as semiconductor-ionization detectors or resolution recovery reconstruction, will be topic of future investigation.

Technetium 99m PSMA Superscan Mimicking a Bone Scan Gone Wrong.

Imaging of metastatic castrate-resistant prostate cancer to select patients suitable for peptide receptor radioligand therapy can be performed with both SPECT and PET PSMA radiotracers. Although PET radiotracers generally have higher sensitivity and spatial resolution, SPECT tracers can be an effective alternative when PET/CT systems are unavailable in the clinical setting. We present a case of a 43-year-old male, who was referred to our facility for workup for radioligand PSMA therapy. His Tc-99m PSMA images revealed diffuse bone infiltration in a pattern mimicking a bone scan.

Contemporary update of SPECT tracers and novelties in radioguided surgery: a perspective based on urology.

Recent technical advances and implementation of novel radiotracers have further increased the potential of radioguided surgery for a broad variety of malignancies. Indeed, the possibilities for future applications of novel radiotracers in diverse oncological strategies has become more promising than ever. This literature review aims to provide a contemporary update on a selected group of radiotracers and evaluates the usability of radioguided surgery and sentinel node procedures, focusing on most promising advances. For example, the impact of targeted radiotracers on prostate specific membrane antigen (PSMA), CD206 receptor-targeted agents (99mTc-tilmanocept), and hybrid tracers adding fluorescence to radioguidance (ICG-99mTc-nanocolloid) as well as targeting hypoxia-induced carbonic anhydrase IX (CAIX) will be covered. Furthermore, future outlooks on the implementation of gold nanoparticles (AuNP's), but also technical advances in improved radiotracer detection by hybrid gamma devices will be discussed.

Optimization of SPECT/CT imaging protocols for quantitative and qualitative 99mTc SPECT

BackgroundThe introduction of hybrid SPECT/CT devices enables quantitative imaging in SPECT, providing a methodological setup for quantitation using SPECT tracers comparable to PET/CT. We evaluated a specific quantitative reconstruction algorithm for SPECT data using a 99mTc-filled NEMA phantom. Quantitative and qualitative image parameters were evaluated for different parametrizations of the acquisition and reconstruction protocol to identify an optimized quantitative protocol.ResultsThe reconstructed activity concentration (ACrec) and the signal-to-noise ratio (SNR) of all examined protocols (n = 16) were significantly affected by the parametrization of the weighting factor k used in scatter correction, the total number of iterations and the sphere volume (all, p < 0.0001). The two examined SPECT acquisition protocols (with 60 or 120 projections) had a minor impact on the ACrec and no significant impact on the SNR.In comparison to the known AC, the use of default scatter correction (k = 0.47) or object-specific scatter correction (k = 0.18) resulted in an underestimation of ACrec in the largest sphere volume (26.5 ml) by − 13.9 kBq/ml (− 16.3%) and − 7.1 kBq/ml (− 8.4%), respectively. An increase in total iterations leads to an increase in estimated AC and a decrease in SNR. The mean difference between ACrec and known AC decreased with an increasing number of total iterations (e.g., for 20 iterations (2 iterations/10 subsets) = − 14.6 kBq/ml (− 17.1%), 240 iterations (24i/10s) = − 8.0 kBq/ml (− 9.4%), p < 0.0001). In parallel, the mean SNR decreased significantly from 2i/10s to 24i/10s by 76% (p < 0.0001).ConclusionQuantitative SPECT imaging is feasible with the used reconstruction algorithm and hybrid SPECT/CT, and its consistent implementation in diagnostics may provide perspectives for quantification in routine clinical practice (e.g., assessment of bone metabolism). When combining quantitative analysis and diagnostic imaging, we recommend using two different reconstruction protocols with task-specific optimized setups (quantitative vs. qualitative reconstruction). Furthermore, individual scatter correction significantly improves both quantitative and qualitative results.

Fully Automated GMP-Compliant Synthesis of [18F]FE-PE2I.

In the struggle to understand and accurately diagnose Parkinson′s disease, radiopharmaceuticals and medical imaging techniques have played a major role. By being able to image and quantify the dopamine transporter density, noninvasive diagnostic imaging has become the gold standard. In the shift from the first generation of SPECT tracers, the fluorine-18-labeled tracer [18F]FE-PE2I has emerged as the agent of choice for many physicians. However, implementing suitable synthesis for the production of [18F]FE-PE2I has proved more challenging than expected. Through a thorough analysis of the relevant factors affecting the final radiochemical yield, we were able to implement high-yielding fully automated GMP-compliant synthesis of [18F]FE-PE2I on a Synthera®+ platform. By reaching RCYs up to 62%, it allowed us to isolate 25 GBq of the formulated product, and an optimized formulation resulted in the shelf life of 6 h, satisfying the increased demand for this radiopharmaceutical.

Efficient Monte-Carlo based system modelling for image reconstruction in preclinical pinhole SPECT

The use of multi-pinhole collimation has enabled ultra-high-resolution imaging of SPECT and PET tracers in small animals. Key for obtaining high-quality images is the use of statistical iterative image reconstruction with accurate energy-dependent photon transport modelling through collimator and detector. This can be incorporated in a system matrix that contains the probabilities that a photon emitted from a certain voxel is detected at a specific detector pixel. Here we introduce a fast Monte-Carlo based (FMC-based) matrix generation method for pinhole imaging that is easy to apply to various radionuclides. The method is based on accelerated point source simulations combined with model-based interpolation to straightforwardly change or combine photon energies of the radionuclide of interest. The proposed method was evaluated for a VECTor PET-SPECT system with (i) a HE-UHR-M collimator and (ii) an EXIRAD-3D 3D autoradiography collimator. Both experimental scans with 99mTc, 111In, and 123I, and simulated scans with 67Ga and 90Y were performed for evaluation. FMC was compared with two currently used approaches, one based on a set of point source measurements with 99mTc (dubbed traditional method), and the other based on an energy-dependent ray-tracing simulation (ray-tracing method). The reconstruction results show better image quality when using FMC-based matrices than when applying the traditional or ray-tracing matrices in various cases. FMC-based matrices generalise better than the traditional matrices when imaging radionuclides with energies deviating too much from the energy used in the calibration and are computationally more efficient for very-high-resolution imaging than the ray-tracing matrices. In addition, FMC has the advantage of easily combining energies in a single matrix which is relevant when imaging radionuclides with multiple photopeak energies (e.g. 67Ga and 111In) or with a continuous energy spectrum (e.g. 90Y). To conclude, FMC is an efficient, accurate, and versatile tool for creating system matrices for ultra-high-resolution pinhole SPECT.

Single Photon Emission Tomography in the Diagnostic Assessment of Cardiac and Vascular Infectious Diseases.

Cardiac and vascular infection is an arising cause of mortality and morbidity in the adult population. Diagnosis based on culture and anatomic imaging are frequently inconclusive. Radiolabeled leucocyte scintigraphy plays a useful role in the diagnosis and management of these serious infectious conditions. In this paper, we present an update on the diagnostic performance of single- photon emission tomographic (SPECT) techniques using different radionuclides in the management of patients with cardiac and vascular infections. We performed a thorough search of recent literature on the topic. We present a discussion on the clinical utility of different SPECT tracers in cardiac and vascular infections, including infective endocarditis, cardiac implantable electronic device (CIED) infections, left ventricular assist device infection, and vascular graft infection. Radionuclide technique using SPECT tracers is a useful imaging modality in the diagnosis of cardiac infection. Among the different SPECT tracers for infection imaging, radiolabeled leucocyte scintigraphy is currently the most useful tool in the diagnosis and management of patients with suspected cardiac and vascular infection. Radiolabeled leucocyte scintigraphy has a high specificity, a result of the ability of the leucocytes to accumulate as sites of pyogenic infection but not at sites of sterile inflammation such as seen in the early post-operative period or in response to the presence of a prosthetic cardiac or vascular material. Limited experience with radiotracers for in vivo labelling of leucocytes such as 99mTc-sulesomab and 99mTc-besilesomab show acceptable diagnostic performance without the need for the tedious process of ex-vivo labeling. 67Ga scintigraphy used to be popular for cardiac and vascular infection imaging. Its use has run out of favor following the availability of more effective molecular imaging methods. SPECT techniques with radiolabeled leucocyte scintigraphy has a high diagnostic performance in the evaluation of patients with suspected cardiac or vascular infection. It is able to confirm or reject the presence of infection when results of anatomic imaging or culture remain inconclusive. Its diagnostic performance is not compromised by sterile inflammation occurring in the early post-operative period or in response to implanted prosthetic materials.

Radio-pharmaceuticals for cancer treatment: are they ready for prime time yet?

Radio-pharmaceuticals for cancer treatment: are they ready for prime time yet?

Les caméras à semi-conducteurs grand champ : le point de vue du radiophysicien

Whole body CZT cameras might clearly enhance single photon emission imaging not only through the optimization of acquisition protocols but also through the development of SPECT tracers with the objective of reaching an image quality comparable to that of PET imaging but with much lower costs and technical constraints.

Initial evaluation of 99m Tc-tricarbonyl-cyclopentadienyl fatty acids derivatives as SPECT tracers for myocardium.

Fatty acids are myocardial metabolic agent for detecting myocardial ischemia and infraction. However, no 99m Tc-labeled fatty acids had potential use in clinical practice. In this study, 99m Tc-CpTT-10-oxo-para-PPA (1d), 99m Tc-CpTT-11-oxo-para-PPA (2d), 99m Tc-CpTT-12-oxo-para-PPA (3d), 99m Tc-CpTT-11-oxo-ortho-PPA (4d), and 99m Tc-CpTT-11-oxo-meta-PPA (5d) were synthesized by a double ligand transfer reaction, and their biological behaviors were investigated. Compound 2d achieved good heart to blood ratio (3.39 at 5min after intravenous), and 2d showed high-heart uptake of 6.20%ID/g at 5minutes after injection. Compound 3d displayed a prolonged retention in the myocardium (1.43%ID/g at 60min after injection). Radioactivity accumulation in the lungs, spleen, and blood was eliminated rapidly. In vivo, metabolite analysis presented that compound 6d may be metabolite of 2d through β-oxidation in tissue. Unfortunately, the biodistribution studies of 1d, 2d, 3d, 4d, and 5d showed fast heart clearance and poor heart to liver ratios, which suggested that the 5 99m Tc-labeled fatty acid analogues cannot be used for diagnosis.

Cardio-oncology: the Nuclear Option.

Cardio-oncology focuses increased effort to decrease cancer treatment-related cardiotoxicity while continuing to improve outcomes. We sought to synthesize the latest in nuclear cardiology as it pertains to the assessment of left ventricular function in preventative guidelines and comparison to other modalities, novel molecular markers of pre-clinical cardiotoxicity, and its role in cardiac amyloid diagnosis. Planar ERNA (equilibrium radionuclide angiocardiography) provides a reliable and proven means of monitoring and preventing anthracycline cardiotoxicity, and SPECT ERNA using solid-state gamma cameras may provide reproducible assessments of left ventricular function with reduced radiation exposure. While certain chemotherapeutics have vascular side effects, the use of stress perfusion imaging has still not been adequately studied for routine use. Similarly, markers of apoptosis, inflammation, and sympathetic nerve dysfunction are promising, but are still not ready for uniform usage. SPECT tracers can assist in nonbiopsy diagnosis of cardiac amyloid. Nuclear cardiology is a significant contributor to the multimodality approach to cardio-oncology.

The widely used SPECT and PET tracers for cardiac sympathetic nervous system

The widely used SPECT and PET tracers for cardiac sympathetic nervous system

FP-CIT- and IBZM-SPECT in Corticobasal Syndrome: Results from a Clinical Follow-Up Study

Objective: To evaluate the striatal presynaptic dopamine transporter (FP-CIT-SPECT) and postsynaptic D₂ receptor (IBZM-SPECT) binding in patients with corticobasal syndrome (CBS). Background: FP-CIT and IBZM are commercially available and approved SPECT tracers for in vivo molecular imaging of pre- and postsynaptic nigrostriatal neuronal degeneration, but only few data for CBS are available. Methods: 23 patients meeting clinical criteria for early- to mid-stage CBS (disease duration ≤4 years) were examined with SPECT radiotracers FP-CIT and IBZM. All suspected CBS patients underwent a clinical follow-up examination and were re-evaluated after 19.7 ± 15.2 months (mean ± SD). Postmortem diagnosis was available for 2 patients. In patients who met research criteria for probable CBS at the final follow-up visit (n = 19; disease duration: 1.95 ± 0.91 years), SPECT binding values were compared to those of age- and gender-matched Parkinson's disease (PD) patients (n = 18, disease duration: 1.92 ± 0.91 years; clinical follow-up: 32 ± 29.6 months) and neurologically normal control subjects (n = 19). Results: In comparison to the healthy control subjects, both patient groups showed significant and asymmetric reduction of the striatal presynaptic dopamine transporter binding, but PD patients had significantly lower FP-CIT binding ratios than probable-CBS patients. FP-CIT binding values of probable-CBS patients and healthy controls demonstrated marked overlaps, and in 7 patients (39%) scans revealed no dopaminergic deficit. IBZM uptake did not show significant between-group differences. Conclusion: Our data indicate that in the early- to mid-stage CBS the degree of nigrostriatal impairment is only mild with a significant proportion of preserved dopamine transporter binding.

Radiosynthesis of SPECT tracers via a copper mediated 123I iodination of (hetero)aryl boron reagents.

A general method for the copper mediated nucleophilic 123I-iodination of (hetero)aryl boronic esters and acids has been developed. The broad substrate scope of this radiosynthetic approach allows access to [123I]DPA-713, [123I]IMPY, [123I]MIBG and [123I]IPEB that are four commonly used SPECT radiotracers. Our results infer that aryl boronic reagents can now be employed as common precursors for both fluorine-18 and iodine-123 radiolabelling.

Hypoxia PET Tracers in EBRT Dose Planning in Head and Neck Cancer.

Over the years, external beam radiotherapy (EBRT) has been used in the treatment management of many malignancies, including head and neck squamous cell carcinomas (HNSCC). Hypoxia is a common feature in HNSCC. Hypoxic segments in HNSCC have proven to be more resistant to radiotherapy. The ability to identify hypoxia using SPECT and PET tracers has been investigated since the late 1970s. Nitroimidazole-based compounds labelled with positron emitters have been developed to more specifically image hypoxia. This article reviews the current data from research publications on(18)F-FMISO, (18)F-FAZA, (18)F-EF5 and (64)Cu-ATSM.