Human Dose Estimation of [⁶⁴Cu]Cu-DOTATATE for PET Imaging of Neuroendocrine Tumors
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Abstract
Objective: The aim of this preclinical study was to evaluate the dosimetry and radiation safety of [64Cu]Cu-DOTATATE, a promising PET radiopharmaceutical for imaging SSTR2-positive neuroendocrine tumors (NETs), and to establish its potential for clinical translation.
Materials and Methods: [64Cu]Cu-DOTATATE was synthesized by radiolabeling DOTATATE with [64Cu]CuCl₂, and its radiochemical purity was assessed using HPLC and RTLC. Biodistribution studies were conducted in rats at 2, 4, 12, and 24 h post-injection, and the organs' radioactivity was measured using an HPGe detector. Dosimetry calculations were performed based on the MIRD schema using animal biodistribution data to estimate absorbed doses in human organs.
Results: [64Cu]Cu-DOTATATE demonstrated excellent radiochemical purity (>99%) and stability over 12 h in PBS and human serum. Biodistribution analysis showed rapid blood clearance and high uptake in SSTR2-expressing organs, such as the pancreas and adrenals, with renal excretion as the primary elimination route. The estimated absorbed doses in key organs were highest in the pancreas (0.205 mGy/MBq), followed by kidneys and liver. Comparative dosimetry with other SSTR-targeted agents, like 68Ga-DOTATATE, revealed similar or lower radiation doses in non-target organs.
Conclusion: [64Cu]Cu-DOTATATE exhibited favorable pharmacokinetics and an acceptable radiation dose profile, supporting its potential as a safe and effective PET imaging agent for SSTR2-positive NETs. The extended half-life of [64Cu] enhances its clinical utility with improved tumor-to-background contrast and centralized production logistics, paving the way for its use in clinical settings.
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9- Mathias Loft et al., "64Cu-DOTATATE PET in patients with neuroendocrine neoplasms: prospective, head-to-head comparison of imaging at 1 hour and 3 hours after injection." Journal of Nuclear Medicine, Vol. 62 (No. 1), pp. 73-80, (2021).
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14- Kimiteru Ito et al., "Phase Ⅰ Study of 64Cu-ATSM Therapy in Malignant Brain Tumors: Safety, Pharmacokinetics, and Preliminary Outcomes." ed: Society of Nuclear Medicine, (2025).
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17- Haochuan Guo et al., "The pivotal role of preclinical animal models in anti-cancer drug discovery and personalized cancer therapy strategies." Pharmaceuticals, Vol. 17 (No. 8), p. 1048, (2024).
18- Samaneh Zolghadri, Fateme Badipa, Naeimeh Amraee, Behrouz Alirezapour, Davood Beiki, and Hassan Yousefnia, "Development and evaluation of [64Cu] Cu-DOTATATE for clinical applications." Iranian Journal of Nuclear Medicine, Vol. 31 (No. 2), pp. 157-66, (2023).
19- Saeid Ranjbar, Seyed Mahmoud Reza Aghamiri, Saeed Rajabifar, Samaneh Zolghadri, and Hassan Yousefnia, "[113mIn] In-RM2: a high potential agent for SPECT imaging of GRPR-expressing tumors." Physical and Engineering Sciences in Medicine, Vol. 48 (No. 1), pp. 273-83, (2025).
20- Leyla Akbari, Sedigheh Sina, Samaneh Zolghadri, Ali Moghaddasi, Kamal Hadad, and Hassan Yousefnia, "[113mIn] In-PSMA: high potential agent for SPECT imaging of prostate cancer." Radiochimica Acta, Vol. 112 (No. 11), pp. 883-94, (2024).
21- Samaneh Zolghadri, Saeed Ranjbar, Fateme Taati, Arezou Karimian, Hassan Yousefnia, and Yohannes Sardjono, "Human dose estimation of a novel SPECT imaging agent using animal experimental data and Monte Carlo simulation." Radiation and Environmental Biophysics, pp. 1-14, (2025).
22- Samaneh Zolghadri, Fatemeh Mohammadpour-Ghazi, and Hassan Yousefnia, "Preclinical studies and absorbed dose estimation of [89Zr] Zr-DFO-Bevacizumab for PET imaging of VEGF-expressing tumors." Applied Radiation and Isotopes, Vol. 210p. 111379, (2024).
23- Eun Young Han, Wesley E Bolch, and Keith F Eckerman, "Revisions to the ORNL series of adult and pediatric computational phantoms for use with the MIRD schema." Health Physics, Vol. 90 (No. 4), pp. 337-56, (2006).
24- ICRP ICRP, "Radiological protection in biomedical research." ICRP Publication, Vol. 62(1992).
25- Hassan Yousefnia, Samaneh Zolghadri, Amir Reza Jalilian, Mojtaba Tajik, and Mohammad Ghannadi-Maragheh, "Preliminary dosimetric evaluation of 166Ho-TTHMP for human based on biodistribution data in rats." Applied Radiation and Isotopes, Vol. 94pp. 260-65, (2014).
26- Walter Stephen Snyder, "" S" absorbed dose per unit cumulated activity for selected radionuclides and organs." MIRD Pamphlet no. 11, (1975).
27- Michael G Stabin, Richard B Sparks, and Eric Crowe, "OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine." Journal of Nuclear Medicine, Vol. 46 (No. 6), pp. 1023-27, (2005).
28- Flavio Forrer et al., "A comparison of 111In-DOTATOC and 111In-DOTATATE: biodistribution and dosimetry in the same patients with metastatic neuroendocrine tumours." European journal of nuclear medicine and molecular imaging, Vol. 31 (No. 9), pp. 1257-62, (2004).
29- Salih Özgüven et al., "Physiological biodistribution of 68Ga-DOTA-TATE in normal subjects." Molecular imaging and radionuclide therapy, Vol. 30 (No. 1), p. 39, (2021).
30- Hassan Yousefnia, Masoumeh-Sadat Mousavi-Daramoroudi, Samaneh Zolghadri, and Fereydoun Abbasi-Davani, "Preparation and biodistribution assessment of low specific activity 177 Lu-DOTATOC for optimization studies." Iranian Journal of Nuclear Medicine, Vol. 24 (No. 2), (2016).
31- Mattias Sandström et al., "Comparative biodistribution and radiation dosimetry of 68Ga-DOTATOC and 68Ga-DOTATATE in patients with neuroendocrine tumors." Journal of Nuclear Medicine, Vol. 54 (No. 10), pp. 1755-59, (2013).
32- MG Stabin et al., "Radiation dosimetry for indium-111-pentetreotide." Journal of Nuclear Medicine, Vol. 38 (No. 12), pp. 1919-22, (1997).
33- Ulrich Knigge Camilla B Johnbeck , Annika Loft , et al., "Head-to-Head Comparison of 64Cu-DOTATATE and 68Ga-DOTATOC PET/CT: A Prospective Study of 59 Patients with Neuroendocrine Tumors." Journal of Nuclear Medicine, Vol. 53 (No. 3), pp. 451-57, (2016).
34- Wei-Ann Hsueh Adam L. Kesner, Johannes Czernin, Henry Padgett, Michael E. Phelps & Daniel H. S. Silverman, "Radiation Dose Estimates for [18F]5-Fluorouracil Derived from PET-Based and Tissue-Based Methods in Rats." Molecular Imaging and Biology, Vol. 10pp. 341–48, (2008).
35- Edalat Radfar, Amir R. Jalilian, Hassan Yousefnia, Ali Bahrami-samani, and Mohammad Ghannadi-Maragheh, "A comparative study of preliminary dosimetry for human based on distribution data in rats with 111In, 90Y, 153Sm, and 177Lu labeled rituximab. ." Nuclear Technology and Radiation Protection, Vol. 27 (No. 2144-151), (2012).
2- James C Yao et al., "One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States." Journal of clinical oncology, Vol. 26 (No. 18), pp. 3063-72, (2008).
3- Pamela L Kunz, "Carcinoid and neuroendocrine tumors: building on success." Journal of clinical oncology, Vol. 33 (No. 16), pp. 1855-63, (2015).
4- Thomas A Hope et al., "Appropriate use criteria for somatostatin receptor PET imaging in neuroendocrine tumors." Journal of Nuclear Medicine, Vol. 59 (No. 1), pp. 66-74, (2018).
5- Marta Opalińska, Karolina Morawiec-Sławek, Adrian Kania-Kuc, Ibraheem Al Maraih, Anna Sowa-Staszczak, and Alicja Hubalewska-Dydejczyk, "Potential value of pre-and post-therapy [68Ga] Ga-DOTA-TATE PET/CT in the prognosis of response to PRRT in disseminated neuroendocrine tumors." Frontiers in Endocrinology, Vol. 13p. 929391, (2022).
6- Mojdeh Naderi, Samaneh Zolghadri, Hassan Yousefnia, Ali Ramazani, and Amir Reza Jalilian, "Preclinical study of 68Ga-DOTATOC: Biodistribution assessment in syrian rats and evaluation of absorbed dose in human organs." Asia Oceania Journal of Nuclear Medicine and Biology, Vol. 4 (No. 1), p. 19, (2016).
7- Carolyn J Anderson and Riccardo Ferdani, "Copper-64 radiopharmaceuticals for PET imaging of cancer: advances in preclinical and clinical research." Cancer Biotherapy and Radiopharmaceuticals, Vol. 24 (No. 4), pp. 379-93, (2009).
8- Anupriya Chhabra and Mathew L Thakur, "Theragnostic radionuclide pairs for prostate cancer management: 64Cu/67Cu, can be a budding hot duo." Biomedicines, Vol. 10 (No. 11), p. 2787, (2022).
9- Mathias Loft et al., "64Cu-DOTATATE PET in patients with neuroendocrine neoplasms: prospective, head-to-head comparison of imaging at 1 hour and 3 hours after injection." Journal of Nuclear Medicine, Vol. 62 (No. 1), pp. 73-80, (2021).
10- Abhishek Jha et al., "Choice Is Good at Times: The Emergence of [64Cu] Cu-DOTATATE–Based Somatostatin Receptor Imaging in the Era of [68Ga] Ga-DOTATATE." Journal of Nuclear Medicine, Vol. 63 (No. 9), p. 1300, (2022).
11- Jason P Holland, Riccardo Ferdani, Carolyn J Anderson, and Jason S Lewis, "Copper-64 radiopharmaceuticals for oncologic imaging." PET clinics, Vol. 4 (No. 1), pp. 49-67, (2009).
12- Samaneh Zolghadri, Fateme Badipa, Hassan Yousefnia, and Zahra Shiri-Yekta, "Development of [64Cu] Cu-BPAMD for PET imaging of bone metastases." Radiochimica Acta, Vol. 112 (No. 4), pp. 247-53, (2024).
13- Bernhard Grubmueller et al., "64Cu-PSMA-617 PET/CT imaging of prostate adenocarcinoma: first in-human studies." Cancer Biotherapy and Radiopharmaceuticals, Vol. 31 (No. 8), pp. 277-86, (2016).
14- Kimiteru Ito et al., "Phase Ⅰ Study of 64Cu-ATSM Therapy in Malignant Brain Tumors: Safety, Pharmacokinetics, and Preliminary Outcomes." ed: Society of Nuclear Medicine, (2025).
15- Andreas Pfeifer et al., "Clinical PET of neuroendocrine tumors using 64Cu-DOTATATE: first-in-humans study." Journal of Nuclear Medicine, Vol. 53 (No. 8), pp. 1207-15, (2012).
16- Camilla B Johnbeck et al., "Head-to-head comparison of 64Cu-DOTATATE and 68Ga-DOTATOC PET/CT: a prospective study of 59 patients with neuroendocrine tumors." Journal of Nuclear Medicine, Vol. 58 (No. 3), pp. 451-57, (2017).
17- Haochuan Guo et al., "The pivotal role of preclinical animal models in anti-cancer drug discovery and personalized cancer therapy strategies." Pharmaceuticals, Vol. 17 (No. 8), p. 1048, (2024).
18- Samaneh Zolghadri, Fateme Badipa, Naeimeh Amraee, Behrouz Alirezapour, Davood Beiki, and Hassan Yousefnia, "Development and evaluation of [64Cu] Cu-DOTATATE for clinical applications." Iranian Journal of Nuclear Medicine, Vol. 31 (No. 2), pp. 157-66, (2023).
19- Saeid Ranjbar, Seyed Mahmoud Reza Aghamiri, Saeed Rajabifar, Samaneh Zolghadri, and Hassan Yousefnia, "[113mIn] In-RM2: a high potential agent for SPECT imaging of GRPR-expressing tumors." Physical and Engineering Sciences in Medicine, Vol. 48 (No. 1), pp. 273-83, (2025).
20- Leyla Akbari, Sedigheh Sina, Samaneh Zolghadri, Ali Moghaddasi, Kamal Hadad, and Hassan Yousefnia, "[113mIn] In-PSMA: high potential agent for SPECT imaging of prostate cancer." Radiochimica Acta, Vol. 112 (No. 11), pp. 883-94, (2024).
21- Samaneh Zolghadri, Saeed Ranjbar, Fateme Taati, Arezou Karimian, Hassan Yousefnia, and Yohannes Sardjono, "Human dose estimation of a novel SPECT imaging agent using animal experimental data and Monte Carlo simulation." Radiation and Environmental Biophysics, pp. 1-14, (2025).
22- Samaneh Zolghadri, Fatemeh Mohammadpour-Ghazi, and Hassan Yousefnia, "Preclinical studies and absorbed dose estimation of [89Zr] Zr-DFO-Bevacizumab for PET imaging of VEGF-expressing tumors." Applied Radiation and Isotopes, Vol. 210p. 111379, (2024).
23- Eun Young Han, Wesley E Bolch, and Keith F Eckerman, "Revisions to the ORNL series of adult and pediatric computational phantoms for use with the MIRD schema." Health Physics, Vol. 90 (No. 4), pp. 337-56, (2006).
24- ICRP ICRP, "Radiological protection in biomedical research." ICRP Publication, Vol. 62(1992).
25- Hassan Yousefnia, Samaneh Zolghadri, Amir Reza Jalilian, Mojtaba Tajik, and Mohammad Ghannadi-Maragheh, "Preliminary dosimetric evaluation of 166Ho-TTHMP for human based on biodistribution data in rats." Applied Radiation and Isotopes, Vol. 94pp. 260-65, (2014).
26- Walter Stephen Snyder, "" S" absorbed dose per unit cumulated activity for selected radionuclides and organs." MIRD Pamphlet no. 11, (1975).
27- Michael G Stabin, Richard B Sparks, and Eric Crowe, "OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine." Journal of Nuclear Medicine, Vol. 46 (No. 6), pp. 1023-27, (2005).
28- Flavio Forrer et al., "A comparison of 111In-DOTATOC and 111In-DOTATATE: biodistribution and dosimetry in the same patients with metastatic neuroendocrine tumours." European journal of nuclear medicine and molecular imaging, Vol. 31 (No. 9), pp. 1257-62, (2004).
29- Salih Özgüven et al., "Physiological biodistribution of 68Ga-DOTA-TATE in normal subjects." Molecular imaging and radionuclide therapy, Vol. 30 (No. 1), p. 39, (2021).
30- Hassan Yousefnia, Masoumeh-Sadat Mousavi-Daramoroudi, Samaneh Zolghadri, and Fereydoun Abbasi-Davani, "Preparation and biodistribution assessment of low specific activity 177 Lu-DOTATOC for optimization studies." Iranian Journal of Nuclear Medicine, Vol. 24 (No. 2), (2016).
31- Mattias Sandström et al., "Comparative biodistribution and radiation dosimetry of 68Ga-DOTATOC and 68Ga-DOTATATE in patients with neuroendocrine tumors." Journal of Nuclear Medicine, Vol. 54 (No. 10), pp. 1755-59, (2013).
32- MG Stabin et al., "Radiation dosimetry for indium-111-pentetreotide." Journal of Nuclear Medicine, Vol. 38 (No. 12), pp. 1919-22, (1997).
33- Ulrich Knigge Camilla B Johnbeck , Annika Loft , et al., "Head-to-Head Comparison of 64Cu-DOTATATE and 68Ga-DOTATOC PET/CT: A Prospective Study of 59 Patients with Neuroendocrine Tumors." Journal of Nuclear Medicine, Vol. 53 (No. 3), pp. 451-57, (2016).
34- Wei-Ann Hsueh Adam L. Kesner, Johannes Czernin, Henry Padgett, Michael E. Phelps & Daniel H. S. Silverman, "Radiation Dose Estimates for [18F]5-Fluorouracil Derived from PET-Based and Tissue-Based Methods in Rats." Molecular Imaging and Biology, Vol. 10pp. 341–48, (2008).
35- Edalat Radfar, Amir R. Jalilian, Hassan Yousefnia, Ali Bahrami-samani, and Mohammad Ghannadi-Maragheh, "A comparative study of preliminary dosimetry for human based on distribution data in rats with 111In, 90Y, 153Sm, and 177Lu labeled rituximab. ." Nuclear Technology and Radiation Protection, Vol. 27 (No. 2144-151), (2012).
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How to Cite
1.
Zolghadri S, Vosoughi S, Salek N, Mehrabi M, Yousefnia H. Human Dose Estimation of [⁶⁴Cu]Cu-DOTATATE for PET Imaging of Neuroendocrine Tumors. Frontiers Biomed Technol. 2026;.
