Search Results (136)

The fibrillary aggregation of α-synuclein is a hallmark of Parkinson’s disease (PD) and a potential target for diagnostics and therapeutics. Although substantial effort has been devoted to the development of positron emission tomography (PET) probes for detecting α-synuclein aggregates, no clinically suitable tracer has been reported. The design and synthesis of 43 new N-(6-methoxypyridin-3-yl)quinolin-2-amine derivatives and an evaluation of their α-synuclein binding affinity is reported here. Compounds 7f, 7j, and 8i exhibited high affinity for α-synuclein and were selected for ¹¹C, ¹⁸F, ¹²⁵I, or ³H radiolabeling. A photoaffinity variant, TZ-CLX, structurally related to 7j and 8i, demonstrated preferential binding to the C-terminal region of α-synuclein fibrils. PET brain imaging studies using [¹¹C]7f, [¹⁸F]7j, and [¹¹C]8i in non-human primates indicated that these three α-synuclein PET tracers penetrated the blood–brain barrier. Both [¹¹C]7f and [¹⁸F]7j showed more favorable brain washout pharmacokinetics than [¹¹C]8i. In vitro binding assays showed that [¹²⁵I]8i is a very potent α-synuclein radioligand, with K_d values of 5 nM for both PD brain tissues and LBD-amplified fibrils; it is also selective for PD tissues versus AD or control tissues. These results strongly suggest that the PET probes based on the N-(6-methoxypyridin-3-yl)quinoline-2-amine scaffold have potential utility in detecting α-synuclein aggregates in vivo. Full article

While multi-parametric magnetic resonance imaging (mpMRI) is known to be a specific and reliable modality for the diagnosis of non-metastatic prostate cancer (PC), positron emission tomography (PET) using ⁶⁸Ga labeled ligands targeting the prostate-specific membrane antigen (PSMA) is known for its reliable detection of prostate cancer, being the most sensitive modality for the assessment of the extra-prostatic extension of the disease and the establishment of a diagnosis, even before biopsy. Background/Objectives: Here, we compared these modalities in regards to the localization of intraprostatic cancer lesions prior to local HDR brachytherapy. Methods: A cohort of 27 patients received both mpMRI and PSMA-PET/CT. Based on 24 intraprostatic segments, two readers each scored the risk of tumor-like alteration in each imaging modality. The detectability was evaluated using receiver operating characteristic (ROC) analysis. The histopathological findings from biopsy were used as the gold standard in each segment. In addition, we applied a patient-based “congruence” concept to quantify the interobserver and intermodality agreement. Results: For the ROC analysis, we included 447 segments (19 patients), with their respective histological references. The two readers of the MRI reached an AUC of 0.770 and 0.781, respectively, with no significant difference (p = 0.75). The PET/CT readers reached an AUC of 0.684 and 0.608, respectively, with a significant difference (p < 0.001). The segment-wise intermodality comparison showed a significant superiority of MRI (AUC = 0.815) compared to PET/CT (AUC = 0.690) (p = 0.006). Via a patient-based analysis, a superiority of MRI in terms of relative agreement with the biopsy result was observed (n = 19 patients). We found congruence scores of 83% (MRI) and 76% (PET/CT, p = 0.034), respectively. Using an adjusted “near total agreement” score (adjacent segments with positive scores of 4 or 5 counted as congruent), we found an increase in the agreement, with a score of 96.5% for MRI and 92.7% for PET/CT, with significant difference (p = 0.024). Conclusions: This study suggests that in a small collective of low-/intermediate risk prostate cancer, mpMRI is superior for the detection of intraprostatic lesions as compared to PSMA-PET/CT. We also found a higher relative agreement between MRI and biopsy as compared to that for PET/CT. However, further studies including a larger number of patients and readers are necessary to draw solid conclusions. Full article

Intercrystal scatter reduces system sensitivity and spatial resolution, a phenomenon that has been extensively studied in positron emission tomography (PET) systems. However, the issue is even more significant in high-energy systems. The purpose of this study is to propose a practical crosstalk rejection technique and demonstrate its applicability in high-energy photon-counting systems. The effect of inter-crystal scattering interactions between ⁶⁰Co γ photons and lutetium yttrium oxyorthosilicate (LYSO) scintillator crystals is investigated through Monte Carlo simulations conducted using the Geant4 toolkit. To suppress the crosstalk phenomenon, a field-programmable gate array (FPGA)-based algorithm is proposed to suppress inter-crystal scattering events, characterized by a time window of 5 nanoseconds and detector window sizes of one or two. The 250 mm Fe steel penetration model is used to evaluate the proposed algorithm, showing improved radiation image quality, particularly with a detector window size of two, which performs better under low-count-rate conditions. Laboratory testing indicates that the proposed algorithm can enhance steel penetration (SP) by 60–70 mm of Fe when compared to the existing current integration system under the same settings. The suggested method has been proven effective in producing higher-quality images and demonstrates good adaptability by adapting the detector window width according to different system count rates. Full article

N-acetylaspartate (NAA) is the second most abundant metabolite in the human brain. Quantifiable amounts of NAA are also present in the blood, but its role in the peripheral tissues is largely unknown. First, we determined the acute effects of insulin administration on NAA concentrations; second, we assessed whether circulating NAA levels associate with markers of central and peripheral insulin sensitivity. A total of 24 persons living with obesity and 19 healthy, lean controls, without neurological disorders, underwent a euglycemic hyperinsulinemic clamp combined with fluorodeoxyglucose positron emission tomography ([¹⁸F]FDG-PET) imaging of the brain, abdomen, and femoral area. Plasma concentrations of NAA were measured at baseline and ~2 h into the clamp using high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS-MS). Glucose uptake (GU) rates were analysed using a fractional uptake rate. Serum acetate levels were also assessed using nuclear magnetic resonance (NMR) metabolomics. From baseline to steady-state, insulin levels increased from a mean level of 66 to 447 pmol/L (p < 0.0001). Over this period, circulating NAA concentrations decreased by 5% (p = 0.01), similarly in both groups. The change in NAA was inversely related with the change in plasma acetate (r = −0.36, p = 0.048). Circulating NAA was associated with waist–hip ratio (rho = −0.54, p = 0.0002), steady-state free fatty acids (rho = −0.44, p = 0.003), and directly with HDL cholesterol (rho = 0.54, p = 0.0002), adiponectin (rho = 0.48, p = 0.003), and whole-body insulin sensitivity (rho = 0.34, p = 0.03). Circulating NAA was directly related with skeletal muscle (rho = 0.42, p = 0.01) and visceral adipose tissue GU (rho = 0.41, p = 0.02). Insulin administration leads to a small decrease in circulating NAA levels, and NAA associates consistently with markers of insulin sensitivity. While plasma NAA may be relevant to aspects of whole-body homeostasis, mechanistic insights are needed. Full article

Background: The prevalence of patients with cardiac sarcoidosis (CS) diagnosed at a subclinical stage has increased; however, their long-term outcomes are not well known. Objectives: To investigate the incidence and predictors of adverse long-term outcomes in newly diagnosed patients with asymptomatic CS. Methods: Forty-three patients with newly diagnosed asymptomatic CS and comprehensive baseline evaluation with cardiovascular magnetic resonance (CMR) were studied. Asymptomatic CS was defined as CS in patients with biopsy-proven extracardiac sarcoidosis without cardiac symptoms but with abnormalities on CMR or positron emission tomography according to Heart Rhythm Society criteria. The primary endpoint was a composite of all-cause mortality, new ventricular arrhythmia or an atrioventricular block requiring cardiac device implantation, and hospitalization for heart failure. Results: Patients had a mean age of 56 ± 11 years and presented with normal left ventricular (LV) ejection fraction (58 ± 4%). A total of 44.2% of patients reached the composite endpoint during 5 years of follow-up. Patients with the primary endpoint were predominantly female (73.7%) and had a significantly higher prevalence of right ventricular (RV) involvement compared to patients without the primary endpoint (RV late gadolinium enhancement (LGE) in 26.3% vs. 4.2%, p = 0.037). In multivariate regression analysis, extensive LV LGE (HR 1.61, 95% CI 1.16–2.04, p = 0.004) and impaired RV global longitudinal strain (GLS) at baseline (HR 0.46, 95% CI 0.24–0.68, p = 0.015) were significantly predictive of the primary endpoint, whereas treatment with corticosteroids after CS diagnosis was significantly associated with improved outcomes (HR 7.69, 95% CI 1.11–11.11, p = 0.044). Conclusions: Newly diagnosed patients with asymptomatic CS have a significant incidence of adverse outcomes after 5 years of follow-up. The extent of LV LGE and impaired RV GLS at baseline predict poor long-term outcomes in asymptomatic CS. Full article

Background/Objectives: The kinase p38α, a member of the mitogen-activated protein kinase (MAPK) family, is activated by external stimuli and plays a crucial role in inflammation, tumor growth, and metabolic disorders. In particular, p38α is involved in thermogenesis and the metabolism of glucose in brown adipose tissue (BAT), and it contributes to the suppression of obesity and diabetes. The noninvasive imaging of activated p38α could help elucidate diverse pathological processes, including metabolic and inflammatory conditions. This study aimed to develop and evaluate a novel fluorine-18-labeled positron emission tomography (PET) probe for imaging activated p38α in vivo. Methods: We designed 6-(4-[¹⁸F]fluoro-2-fluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)-pyrido[2,3-d]pyrimidin-7(8H)-one ([¹⁸F]R1487) by replacing a fluorine atom in R1487, which is a highly selective p38α inhibitor, with ¹⁸F. A tributylstannyl precursor was reacted with [¹⁸F]KF in the presence of a copper catalyst to synthesize [¹⁸F]R1487. Biodistribution studies and PET/computed tomography (CT) were performed on normal mice to evaluate the in vivo potential of [¹⁸F]R1487. Results: [¹⁸F]R1487 was obtained with a decay-corrected radiochemical conversion of 30.6 ± 5.6% and a decay-corrected radiochemical yield of 6.9 ± 3.6% with a radiochemical purity of >99% after reversed-phase high-performance liquid chromatography purification. The biodistribution study demonstrated high and rapid radioactivity accumulation in BAT (16.3 ± 2.7 %ID/g at 5 min post-injection), with a consistently high BAT-to-blood ratio (>5 over 2 h post-injection). PET/CT imaging successfully visualized BAT with high contrast. Conclusions: These results suggest that [¹⁸F]R1487 is a promising PET probe for imaging activated p38α in vivo, which has potential applications for pathophysiological conditions such as inflammation, cancer, and metabolic disorders. Full article

Background/Objectives: Clinically evident portal hypertension (CEPH) is a major risk factor for the development and poor outcomes of hepatocellular carcinoma (HCC). The aim of this study was to determine the impact of CEPH on the risk of HCC recurrence following liver transplantation (LT). Methods: A total of 129 HCC patients were included in this retrospective analysis. The definition of CEPH was based on indirect clinical features without hepatic venous pressure gradient measurement. The impact of CEPH on the post-LT risk of HCC recurrence was determined by uni- and multivariate analysis. Results: Evidence of manifest portal hypertension (PH) was associated with a higher ¹⁸F-fluorodeoxy-glucose (FDG) uptake of HCC on positron emission tomography (PET; p < 0.001) and increased serum levels of C-reactive protein (p = 0.008) and interleukin−6 (IL-6; p = 0.001). The cumulative risk of HCC recurrence at 5 years post-LT was significantly higher in the CEPH group (38.1% vs. 10.6%, p < 0.001). The eligibility for neoadjuvant transarterial chemoembolization (TACE) was comparable between both study cohorts (71.4% vs. 74.2%; p = 0.719). However, the post-interventional pathologic response rate was significantly lower in the case of PH (15.6% vs. 53.1%; p < 0.001). In addition to the Milan criteria (MC), ¹⁸F-FDG avidity on PET and serum values of IL-6 and alfa-fetoprotein, we identified CEPH as another significant and independent predictor of HCC recurrence (p = 0.008). Conclusions: CEPH correlates with an unfavorable tumor phenotype, TACE refractoriness and a risk of post-LT HCC recurrence. Therefore, the clinical features of PH should be implemented in pre-transplant risk assessment and decision-making processes. Full article

Background/Objectives: Emerging hybrid imaging modalities, like Positron Emission Tomography/Computed Tomography (PET/CT) and Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI), are useful for assessing head and neck cancer (HNC) and its prognosis during follow-up. PET/MRI systems enable simultaneous PET and MRI scans within a single session. These combined PET/MRI scanners merge MRI’s better soft tissue contrast and the molecular metabolic information offered by PET. Aim: To review scientific articles on the use of hybrid PET/MRI techniques in diagnosing dentomaxillofacial malignancies. Method: The available literature on the use of PET/MRI for the diagnosis of dentomaxillofacial malignancies in four online databases (Scopus, PubMed, Web of Science, and the Cochrane Library) was searched. Eligible for this review were original full-text articles on PET/MRI imaging, published between January 2010 and November 2024, based on experimental or clinical research involving humans. Results: Out of the 783 articles retrieved, only twelve articles were included in this systematic review. Nearly half of the articles (5 out of 12) concluded that PET/MRI is superior to PET, MRI, and PET/CT imaging in relation to defining malignancies’ size. Six articles found no statistically significant results and the diagnostic accuracy presented was similar in PET/MRI versus MRI and PET/CT images. Regarding the overall risk of bias, most articles had a moderate risk. Conclusions: The use of PET/MRI in HNC cases provides a more accurate diagnosis regarding dimensions of the tumor and thus a more accurate surgical approach if needed. Further prospective studies on a larger cohort of patients are required to obtain more accurate results on the application of hybrid PET/MRI. Full article

Background/Objectives: Radiotheranostics of neurotensin subtype 1 receptor (NTS₁R)-expressing tumors, like pancreatic, gastrointestinal, or prostate cancer, has attracted considerable attention in recent years. Still, the fast degradation of neurotensin (NT)-based radioligands, by angiotensin-converting enzyme (ACE), neprilysin (NEP), and other proteases, has considerably compromised their efficacy. The recently introduced [^99mTc]Tc-DT11 (DT11, N₄-Lys(MPBA-PEG4)-Arg-Arg-Pro-Tyr-Ile-Leu-OH; N₄, 6-(carboxy)-1,4,8,11-tetraazaundecane) has displayed promising uptake in NTS₁R-positive tumors in mice and enhanced resistance to both ACE and NEP by virtue of the lateral MPBA-PEG4 (MPBA, 4-(4-methylphenyl)butyric acid; PEG4, 14-amino-3,6,9,12-tetraoxatetradecan-1-oic acid) chain attached to the ε-NH₂ of Lys⁷. We were next interested in investigating whether these qualities could be retained in DT14D, likewise modified at Lys⁷ but carrying the universal chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) via a (βAla)₃ spacer at the α-NH₂ of Lys⁷. This chelator switch enables the labeling of DT14D with a wide range of trivalent radiometals suitable for true theranostic applications, not restricted to the diagnostic imaging of NTS₁R-positive lesions only by single-photon emission computed tomography (SPECT). Methods: DT14D was labeled with Ga-67 (a surrogate for the positron emission tomography radionuclide Ga-68), In-111 (for SPECT), and Lu-177 (applied in radiotherapy). The resulting radioligands were tested in NTS₁R-expressing pancreatic cancer AsPC-1 cells and mice models. Results: [⁶⁷Ga]Ga/[¹¹¹In]In/[¹⁷⁷Lu]Lu-DT14D displayed high affinity for human NTS₁R and internalization in AsPC-1 cells. They remained >70% intact 5 min after entering the mice’s circulation, displaying NTS₁R-specific uptake in AsPC-1 xenografts. Conclusions: Suitably side-chain modified NT analogs show enhanced metabolic stability and hence better prospects for radiotheranostic application in NTS₁R-positive cancer. Full article

Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), the asymptomatic precursors to multiple myeloma, affect up to 5% of the population over the age of 40. Bone involvement, a myeloma-defining event, represents a major source of morbidity for patients. Key goals for the management of myeloma precursor conditions include (1) identifying patients at the highest risk for progression to MM with bone involvement and (2) differentiating precursor states from active myeloma requiring treatment. Computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET)-CT with [¹⁸F]fluorodeoxyglucose (FDG) have improved sensitivity for the detection of myeloma bone disease compared to traditional skeletal surveys, and such advanced imaging also provides this field with better tools for detecting early signs of progression. Herein, we review the data supporting the use of advanced imaging for both diagnostics and prognostication in myeloma precursor conditions. Full article

The overexpression of the epidermal growth factor receptor (EGFR) in certain types of prostate cancers and glioblastoma makes it a promising target for targeted radioligand therapy. In this context, pairing an EGFR-targeting peptide with the emerging theranostic pair comprising the Auger electron emitter cobalt-58m (^58mCo) and the Positron Emission Tomography-isotope cobalt-55 (⁵⁵Co) would be of great interest for creating novel radiopharmaceuticals for prostate cancer and glioblastoma theranostics. In this study, GE11 (YHWYGYTPQNVI) was investigated for its EGFR-targeting potential when conjugated using click chemistry to N1-((triazol-4-yl)methyl)-N1,N2,N2-tris(pyridin-2-ylmethyl)ethane-1,2-diamine (TZTPEN). This chelator is suitable for binding Co²⁺ and Co³⁺. With cobalt-57 (⁵⁷Co) serving as a surrogate radionuclide for ^55/58mCo, the novel GE11-TZTPEN construct was successfully radiolabeled with a high radiochemical yield (99%) and purity (>99%). [⁵⁷Co]Co-TZTPEN-GE11 showed high stability in PBS (pH 5) and specific uptake in EGFR-positive cell lines. Disappointingly, no tumor uptake was observed in EGFR-positive tumor-bearing mice, with most activity being accumulated predominantly in the liver, gall bladder, kidneys, and spleen. Some bone uptake was also observed, suggesting in vivo dissociation of ⁵⁷Co from the complex. In conclusion, [⁵⁷Co]Co-TZTPEN-GE11 shows poor pharmacokinetics in a mouse model and is, therefore, not deemed suitable as a targeting radiopharmaceutical for EGFR. Full article

Background/Objectives: Medullary thyroid carcinoma (MTC) is a highly aggressive tumor, as it is characterized by a high probability of local recurrence and distant metastases, even after surgical treatment. Early detection of disease recurrence is critical for improving long-term treatment outcomes and overall patient survival. By comparing different radiopharmaceuticals, this analysis aimed to strengthen existing guidelines and help bridge the gap between the recommendations of the ESMO and the ATA, highlighting the importance of PET/CT scanning in the postoperative follow-up of patients with MTC. Methods: This research was carried out using three searchable databases, PubMed, ScienceDirect, and ResearchGate, resulting in 575 bibliographic studies up to the date of 20 June 2024. A meta-analysis of diagnostic accuracy was performed using the software Meta—DiSc, Version: 2.0 (Universidad Complutense, Barcelona, Spain), which led to aggregate assessments and the design of the SROC. Results: A quality assessment of the eligible studies was conducted, and the key findings were summarized. Conclusions: Regardless of methodology, PET/CT scanning exhibits high sensitivity and specificity values in the diagnosis of local recurrence and metastases in surgical patients with medullary thyroid carcinoma. Furthermore, based on a comparative analysis of18F-FDG and GA68-DOTATE, it appears that these misunderstood radiopharmaceuticals are particularly sensitive and reliable for highlighting MTC, and it was found that there were no statistical differences in terms of sensitivity and specificity. Therefore, these two modalities appear to be complementary in monitoring MTC patients. Full article

Objectives: The objectives of this study were (1) to systematically review the currently used definitions of incidental 2-deoxy-2-[¹⁸F]fluoro-D-glucose positron emission tomography/computed tomography findings (IPFs) in the literature and (2) to propose an IPF definition. Methods: A systematic search was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. The search was guided by the question “How is IPF defined?” and was performed in MEDLINE, Embase, and the Cochrane Library. The retrieved studies were reviewed and analyzed. The definitions of IPFs in the included studies were compiled into two sets of categories based on the description of FDG uptake and the specification of clinical factors in defining IPFs. Results: The systematic literature search identified 4852 publications accessible for title–abstract screening, which yielded 395 studies for full-text assessment. Sixty-five studies met the eligibility criteria and were included. Sixty-two percent mentioned “FDG uptake” in their definition. In 40% of the definitions, “Focal FDG uptake” was specified, while “FDG uptake in the surrounding tissue” was included in 15%. Fifty-seven percent stated that IPFs were “Unrelated to PET/CT indication”. Thirty-four percent specified IPFs as “Present in other organ than PET/CT indication”, whereas 20% included “No known disease related to IPF”. Seventeen percent of the definitions comprised a “New finding”, while 15% and 11% encompassed a “Clinical asymptomatic patient” and “Not a metastasis”, respectively. Finally, 5% of the definitions included “Potential clinical significance”. Conclusions: No generally accepted definition of IPFs currently exists. We propose an IPF definition based on explicit FDG uptake and clinical patient-related factors. Full article

In the evaluation of a patient’s primary hematologic malignancy, positron emission tomography/computed tomography (PET/CT) imaging may incidentally detect a concerning abnormality suggestive of a second concurrent cancer. Despite accounting for nearly 10% of all cancers diagnosed in Canada, there has yet to be a systematic review focused on the prevalence and significance of these incidental PET/CT findings in the context of primary hematologic malignancies. As such, a systematic search strategy was employed on MEDLINE and Embase to document the prevalence and clinical significance of incidental PET/CT findings suggestive of a second concurrent cancer detected in patients evaluated for their primary hematologic malignancy. Thirteen studies published between 2008 and 2022 were reviewed, including conference abstracts (n = 8) and journal articles (n = 5). Clinically significant incidental cancers were detected with a median of 2.4% (range: 1.1–10.3%) in patients with myeloma/plasma cell disorders, compared to a median of 1.5% (range: 0.3–2.8%) in patients with lymphoproliferative diseases. The most common anatomic regions of clinically significant incidental malignancies were identified in the gastrointestinal tract (44.4%), followed by the thyroid gland (22.2%) and lungs (7.9%). In most cases, early detection of incidental cancers led to successful early interventions. PET/CT scans occasionally identify second primary malignancies that require additional attention. These findings may affect the treatment of a patient’s primary hematologic malignancy, and as such, timely coordinated management is important for improved outcomes. This review may inform physicians and administrators of the risk of incidental second malignancies and may highlight a need for enhanced cancer treatment pathways. Full article

We present the case of a 60-year-old male with recurrent atypical meningioma in the right parietal lobe, previously treated with surgery and radiation therapy. Magnetic resonance imaging (MRI) performed 5 years after radiation therapy suggested a possible recurrence. A somatostatin receptor positron emission tomography/computed tomography (SR-PET/CT) scan with Gallium-68 DOTATATE was performed to confirm this suspicion. SR-PET/CT confirmed the presence of recurrent meningioma, showing a novel “rosary sign” with multiple adjacent areas of focal tracer uptake along the resection margins of the previous surgical site in the right parietal region. This novel imaging pattern improved diagnostic accuracy by detailing disease extent and identifying additional lesions not visible via MRI. Given the failure of prior treatments and high SR expression, peptide receptor radionuclide therapy (PRRT) was proposed as a therapeutic option for the patient. Full article