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[99mTc]Tc-DGA1, a Promising CCK2R-Antagonist-Based Tracer for Tumor Diagnosis with Single-Photon Emission Computed Tomography.

ABSTRACT: Radiolabeled gastrin analogues have been proposed for theranostics of cholecystokinin subtype 2 receptor (CCK2R)-positive cancer. Peptide radioligands based on other receptor antagonists have displayed superior pharmacokinetics and higher biosafety than agonists. Here, we present DGA1, a derivative of the nonpeptidic CCK2R antagonist Z-360 carrying an acyclic tetraamine, for [99mTc]Tc labeling. Preclinical comparison of [99mTc]Tc-DGA1 with [99mTc]Tc-DG2 (CCK2R-agonist reference) was conducted in HEK293-CCK2R/CCK2i4svR cells and mice models, qualifying [99mTc]Tc-DGA1 for further study in patients with CCK2R-positive tumors and single-photon emission computed tomography/CT.

SUBMITTER: Kaloudi A

PROVIDER: S-EPMC7429258 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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[99mTc]Tc-DGA1, a Promising CCK2R-Antagonist-Based Tracer for Tumor Diagnosis with Single-Photon Emission Computed Tomography.

Kaloudi Aikaterini A Kanellopoulos Panagiotis P Radolf Thorsten T Chepurny Oleg G OG Rouchota Maritina M Loudos George G Andreae Fritz F Holz George G GG Nock Berthold Artur BA Maina Theodosia T

Molecular pharmaceutics 20200707 8

Radiolabeled gastrin analogues have been proposed for theranostics of cholecystokinin subtype 2 receptor (CCK2R)-positive cancer. Peptide radioligands based on other receptor antagonists have displayed superior pharmacokinetics and higher biosafety than agonists. Here, we present DGA1, a derivative of the nonpeptidic CCK2R antagonist Z-360 carrying an acyclic tetraamine, for [99mTc]Tc labeling. Preclinical comparison of [99mTc]Tc-DGA1 with [99m</s ...[more]

PMID: 32568549

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Project description:BackgroundAlthough small bowel bleeding is relatively rare, it is a potentially fatal disease, and its diagnosis still faces challenges. Technetium 99m-labeled red blood cell computed single photon emission computed tomography/computed tomography (99mTc-RBC SPECT/CT) and contrast-enhanced multidetector computed tomography (MDCT) are common imaging methods for diagnosing small bowel bleeding, but there have been no studies comparing their diagnostic efficacy for this purpose. This study aims to compare the diagnostic value of 99mTc-RBC SPECT/CT and contrast-enhanced MDCT for small bowel bleeding.MethodsA total of 44 patients (30 males and 14 females, median age of 64 years) definitively diagnosed with small bowel bleeding and 15 non-small bowel bleeding patients (8 males and 7 females, median age of 66 years) were consecutively included in this study. All patients underwent 99mTc-RBC SPECT/CT and contrast-enhanced MDCT examinations at Beijing Friendship Hospital of Capital Medical University between January 2020 to September 2023. The definitive diagnosis had been made through surgery or colonoscopy, or through patient history, patient management, and clinical follow-up. We collected clinical data of the participants. 99mTc-RBC SPECT/CT and contrast-enhanced MDCT were reviewed in a blinded fashion for accuracy of detection of active bleeding as well as the active small bowel bleeding location.ResultsAmong the 59 patients, the accuracy, sensitivity, and specificity of 99mTc-RBC SPECT were 27.3%, 93.3%, and 92.3%; for 99mTc-RBC SPECT/CT they were 76.3%, 40.5%, and 93.3%; whereas for contrast-enhanced MDCT they were 45.8%, 27.3%, and 100%, respectively. The diagnostic accuracy of 99mTc-RBC SPECT/CT for jejunal and ileal bleeding was high, at 100% and 86.4%, respectively. Meanwhile, 99mTc-RBC SPECT/CT had a higher accuracy in diagnosing more causes of small bowel bleeding. In 59 patients, the combination of 99mTc-RBC SPECT/CT and contrast-enhanced MDCT accurately diagnosed small bowel bleeding and provided precise localization in 50 patients, resulting in the accuracy, sensitivity, and specificity of 84.7%, 79.5%, and 100.0%, respectively.Conclusions99mTc-RBC SPECT/CT has high diagnostic value in diagnosing small bowel bleeding and is superior to 99mTc-RBC SPECT and contrast-enhanced MDCT. The combination of 99mTc-RBC SPECT/CT and contrast-enhanced MDCT can further improve the diagnostic accuracy of diagnosis, and can accurately guide the diagnosis and treatment of small bowel bleeding.

Project description:PurposeSentinel lymph node (SLN) biopsy has proven to reliably stage the clinically negative neck in early-stage oral squamous cell carcinoma (OSCC). [99mTc]Tc-tilmanocept may be of benefit in OSCC with complex lymphatic drainage patterns and close spatial relation to SLNs.MethodsA prospective within-patient evaluation study was designed to compare [99mTc]Tc-tilmanocept with [99mTc]Tc-nanocolloid for SLN detection. A total of 20 patients with early-stage OSCC were included, who underwent lymphoscintigraphy with both tracers. Both lymphoscintigraphic images of each patient were evaluated for SLN detection and radiotracer distribution at 2-4 h post-injection.ResultsThe injection site's remaining radioactivity was significantly lower for [99mTc]Tc-tilmanocept (29.9%), compared with [99mTc]Tc-nanocolloid (60.9%; p < 0.001). Radioactive uptake in SLNs was significantly lower for [99mTc]Tc-tilmanocept (1.95%) compared with [99mTc]Tc-nanocolloid (3.16%; p = 0.010). No significant difference was seen in SLN to injection site ratio in radioactivity between [99mTc]Tc-tilmanocept (0.066) and [99mTc]Tc-nanocolloid (0.054; p = 0.232). A median of 3.0 and 2.5 SLNs were identified with [99mTc]Tc-tilmanocept and [99mTc]Tc-nanocolloid, respectively (p = 0.297). Radioactive uptake in higher echelon nodes was not significantly different between [99mTc]Tc-tilmanocept (0.57%) and [99mTc]Tc-nanocolloid (0.86%) (p = 0.052). A median of 2.0 and 2.5 higher echelon nodes was identified with [99mTc]Tc-tilmanocept and [99mTc]Tc-nanocolloid, respectively (p = 0.083).Conclusion[99mTc]Tc-tilmanocept had a higher injection site clearance, but at the same time a lower uptake in the SLN, resulting in an SLN to injection site ratio, which was not significantly different from [99mTc]Tc-nanocolloid. The relatively low-radioactive uptake in SLNs of [99mTc]Tc-tilmanocept may limit intraoperative detection of SLNs, but can be overcome by a higher injection dose.

Project description:BackgroundImaging of cell death can provide an early indication of treatment response in cancer. [99mTc]Tc-Duramycin is a small-peptide SPECT tracer that recognizes both apoptotic and necrotic cells by binding to phosphatidylethanolamine present in the cell membrane. Preclinically, this tracer has shown to have favorable pharmacokinetics and selective tumor accumulation early after the onset of anticancer therapy. In this first-in-human study, we report the safety, biodistribution and internal radiation dosimetry of [99mTc]Tc-Duramycin in healthy human volunteers.ResultsSix healthy volunteers (3 males, 3 females) were injected intravenously with [99mTc]Tc-Duramycin (dose: 6 MBq/kg; 473 ± 36 MBq). [99mTc]Tc-Duramycin was well tolerated in all subjects, with no serious adverse events reported. Following injection, a 30-min dynamic planar imaging of the abdomen was performed, and whole-body (WB) planar scans were acquired at 1, 2, 3, 6 and 23 h post-injection (PI), with SPECT acquisitions after each WB scan and one low-dose CT after the first SPECT. In vivo 99mTc activities were determined from semi-quantitative analysis of the images, and time-activity curves were generated. Residence times were calculated from the dynamic and WB planar scans. The mean effective dose was 7.61 ± 0.75 µSv/MBq, with the kidneys receiving the highest absorbed dose (planar analysis: 43.82 ± 4.07 µGy/MBq, SPECT analysis: 19.72 ± 3.42 μGy/MBq), followed by liver and spleen. The median effective dose was 3.61 mSv (range, 2.85-4.14). The tracer cleared slowly from the blood (effective half-life of 2.0 ± 0.4 h) due to high plasma protein binding with < 5% free tracer 3 h PI. Excretion was almost exclusively renal.Conclusion[99mTc]Tc-Duramycin demonstrated acceptable dosimetry (< 5 mSv) and a favorable safety profile. Due to slow blood clearance, optimal target-to-background ratios are expected 5 h PI. These data support the further assessment of [99mTc]Tc-Duramycin for clinical treatment response evaluation.Trial registrationNCT05177640, Registered April 30, 2021, https://clinicaltrials.gov/study/NCT05177640 .

Dataset Information

[99mTc]Tc-DGA1, a Promising CCK2R-Antagonist-Based Tracer for Tumor Diagnosis with Single-Photon Emission Computed Tomography.

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[<sup>99m</sup>Tc]Tc-DGA1, a Promising CCK<sub>2</sub>R-Antagonist-Based Tracer for Tumor Diagnosis with Single-Photon Emission Computed Tomography.

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