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[⁶⁸Ga]Ga-DATA^5m-LM4, a PET Radiotracer in the Diagnosis of SST₂R-Positive Tumors: Preclinical and First Clinical Results.

ABSTRACT: Radiolabeled somatostatin subtype 2 receptor (SST2R)-antagonists have shown advantageous profiles for cancer theranostics compared with agonists. On the other hand, the newly introduced hybrid chelator (6-pentanoic acid)-6-(amino)methyl-1,4-diazepinetriacetate (DATA^5m) rapidly binds Ga-68 (t_1/2: 67.7 min) at much lower temperature, thus allowing for quick access to "ready-for-injection" [⁶⁸Ga]Ga-tracers in hospitals. We herein introduce [⁶⁸Ga]Ga-DATA^5m-LM4 for PET/CT imaging of SST₂R-positive human tumors. LM4 was obtained by 4Pal³/Tyr³-substitution in the known SST₂R antagonist LM3 (H-DPhe-c[DCys-Tyr-DAph(Cbm)-Lys-Thr-Cys]-DTyr-NH₂) and DATA^5m was coupled at the N-terminus for labeling with radiogallium (Ga-67/68). [⁶⁷Ga]Ga-DATA^5m-LM4 was evaluated in HEK293-SST₂R cells and mice models in a head-to-head comparison with [⁶⁷Ga]Ga-DOTA-LM3. Clinical grade [⁶⁸Ga]Ga-DATA^5m-LM4 was prepared and injected in a neuroendocrine tumor (NET) patient for PET/CT imaging. DATA^5m-LM4 displayed high SST₂R binding affinity. [⁶⁷Ga]Ga-DATA^5m-LM4 showed markedly higher uptake in HEK293-SST₂R cells versus [⁶⁷Ga]Ga-DOTA-LM3 and was stable in vivo. In HEK293-SST₂R xenograft-bearing mice, it achieved longer tumor retention and less kidney uptake than [⁶⁷Ga]Ga-DOTA-LM3. [⁶⁸Ga]Ga-DATA^5m-LM4 accurately visualized tumor lesions with high contrast on PET/CT. In short, [⁶⁸Ga]Ga-DATA^5m-LM4 has shown excellent prospects for the PET/CT diagnosis of SST₂R-positive tumors, further highlighting the benefits of Ga-68 labeling in a hospital environment via the DATA^5m-chelator route.

SUBMITTER: Kanellopoulos P

PROVIDER: S-EPMC9740503 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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[68Ga]Ga-DATA5m-LM4, a PET Radiotracer in the Diagnosis of SST2R-Positive Tumors: Preclinical and First Clinical Results.

Kanellopoulos Panagiotis P Nock Berthold A BA Greifenstein Lukas L Baum Richard P RP Roesch Frank F Maina Theodosia T

International journal of molecular sciences 20221123 23

Radiolabeled somatostatin subtype 2 receptor (SST2R)-antagonists have shown advantageous profiles for cancer theranostics compared with agonists. On the other hand, the newly introduced hybrid chelator (6-pentanoic acid)-6-(amino)methyl-1,4-diazepinetriacetate (DATA5m) rapidly binds Ga-68 (t1/2: 67.7 min) at much lower temperature, thus allowing for quick access to "ready-for-injection" [68Ga]Ga-tracers in hospitals. We herein introduce [68Ga]Ga-DATA<s ...[more]

PMID: 36498918

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Project description:It is estimated that melanoma accounted for 76,380 new cases and 10,130 deaths in the United States in 2016. The melanocortin 1 receptor (MC1R) is highly expressed in the vast majority of melanomas, which makes it an attractive target for molecular imaging and radionuclide therapy. Lactam bridge-cyclized α-melanocyte-stimulating hormone (Ac-Nle4-cyclo[Asp5-His-D-Phe7-Arg-Trp-Lys10]-NH2, or Nle-CycMSHhex) analogues have been successfully developed and studied for MC1R-targeted imaging, predominantly with single-photon emission computed tomography (SPECT). The goal of this study was to design and evaluate novel peptides for melanoma imaging with positron emission tomography (PET). We designed and synthesized three peptides, DOTA-PEG2-Nle-CycMSHhex (CCZ01047), DOTA-4-amino-(1-carboxymethyl) piperidine (Pip)-Nle-CycMSHhex (CCZ01048), and DOTA-Pip-Pip-Nle-CycMSHhex (CCZ01056). All three peptides exhibited high binding affinity to MC1R with sub-nanomolar Ki values, rapid internalization into B16F10 melanoma cells and high in vivo stability with more than 93% remaining intact at 15 min post-injection (p.i.) in blood plasma. All three 68Ga-labeled tracers produced high contrast PET images in C57BL/6J mice bearing B16F10 tumors, and their respective tumor uptakes were 8.0 ± 3.0, 12.3 ± 3.3, and 6.5 ± 1.4 %ID/g at 1 h p.i. Minimal normal organ activity was observed at 1 h p.i., except for kidneys (5.1 ± 1.4, 4.7 ± 0.5, and 6.2 ± 2.0 %ID/g, respectively), and thyroid (4.1 ± 0.6 %ID/g for CCZ01047 and 2.4 ± 0.6 %ID/g for CCZ01048). Due to high accumulation at tumor sites and rapid background clearance of 68Ga-CCZ01048, we further evaluated it at 2 h p.i., and a tumor uptake of 21.9 ± 4.6 %ID/g was observed, with background activity further decreased. Exceptional image contrast was also achieved, i.e. tumor-to-blood, tumor-to-muscle, tumor-to-bone and tumor-to-kidney ratios were 96.4 ± 13.9, 210.9 ± 20.9, 39.6 ± 11.9 and 4.0 ± 0.9, respectively. A blocking study was also performed by co-injection of excess amount of non-radioactive Ga-coupled of CCZ01048, which confirmed that the tumor uptake was MC1R mediated. In conclusion, the introduction of a cationic Pip linker to Nle-CycMSHhex, CCZ01048, not only improved tumor uptake, but also generated high tumor-to-normal tissue contrast with PET imaging in a preclinical melanoma model. Therefore, CCZ01048 is a promising candidate for PET imaging of melanoma, and potentially as a theranostic agent for radionuclide therapy of melanoma when labeled with α or β emitters.

Project description:IntroductionThe yield per elution of a 68Ge/68Ga generator decreases during its lifespan. This affects the number of patients injected per elution or the injected dose per patient, thereby negatively affecting the cost of examinations and the quality of PET images due to increased image noise. We aimed to investigate whether AI-based PET denoising can offset this decrease in image quality parameters.MethodsAll patients addressed to our PET unit for a 68Ga-DOTATOC PET/CT from April 2020 to February 2021 were enrolled. Forty-four patients underwent their PET scans according to Protocol_FixedDose (150 MBq) and 32 according to Protocol_WeightDose (1.5 MBq/kg). Protocol_WeightDose examinations were processed using the Subtle PET software (Protocol_WeightDoseAI). Liver and vascular SUV mean were recorded as well as SUVmax, SUVmean and metabolic tumour volume (MTV) of the most intense tumoural lesion and its background SUVmean. Liver and vascular coefficients of variation (CV), tumour-to-background and tumour-to-liver ratios were calculated.ResultsThe mean injected dose of 2.1 (0.4) MBq/kg per patient was significantly higher in the Protocol_FixedDose group as compared to 1.5 (0.1) MBq/kg for the Protocol_WeightDose group. Protocol_WeightDose led to noisier images than Protocol_FixedDose with higher CVs for liver (15.57% ± 4.32 vs. 13.04% ± 3.51, p = 0.018) and blood-pool (28.67% ± 8.65 vs. 22.25% ± 10.37, p = 0.0003). Protocol_WeightDoseAI led to less noisy images than Protocol_WeightDose with lower liver CVs (11.42% ± 3.05 vs. 15.57% ± 4.32, p < 0.0001) and vascular CVs (16.62% ± 6.40 vs. 28.67% ± 8.65, p < 0.0001). Tumour-to-background and tumour-to-liver ratios were lower for protocol_WeightDoseAI: 6.78 ± 3.49 vs. 7.57 ± 4.73 (p = 0.01) and 5.96 ± 5.43 vs. 6.77 ± 6.19 (p < 0.0001), respectively. MTVs were higher after denoising whereas tumour SUVmax were lower: the mean% differences in MTV and SUVmax were + 11.14% (95% CI = 4.84-17.43) and -3.92% (95% CI = -6.25 to -1.59).ConclusionThe degradation of PET image quality due to a reduction in injected dose at the end of the 68Ge/68Ga generator lifespan can be effectively counterbalanced by using AI-based PET denoising.

Dataset Information

[⁶⁸Ga]Ga-DATA^5m-LM4, a PET Radiotracer in the Diagnosis of SST₂R-Positive Tumors: Preclinical and First Clinical Results.

Publications

[<sup>68</sup>Ga]Ga-DATA<sup>5m</sup>-LM4, a PET Radiotracer in the Diagnosis of SST<sub>2</sub>R-Positive Tumors: Preclinical and First Clinical Results.

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