Are radiogallium-labelled DOTA-conjugated somatostatin analogues superior to those labelled with other radiometals?

Purpose: Gallium-68 is a metallic positron emitter with a half-life of 68min that is ideal for the in vivo use of small molecules, such as [68Ga-DOTA,Tyr3]octreotide, in the diagnostic imaging of somatostatin receptor-positive tumours. In preclinical studies it has shown a striking superiority over its 111In-labelled congener. The purpose of this study was to evaluate whether third-generation somatostatin-based, radiogallium-labelled peptides show the same superiority. Methods: Peptides were synthesised on solid phase. The receptor affinity was determined by in vitro receptor autoradiography. The internalisation rate was studied in AR4-2J and hsst-HEK-transfected cell lines. The pharmacokinetics was studied in a rat xenograft tumour model, AR4-2J. Results: All peptides showed high affinities on hsst2, with the highest affinity for the GaIII-complexed peptides. On hsst3 the situation was reversed, with a trend towards lower affinity of the GaIII peptides. A significantly increased internalisation rate was found in sst2-expressing cells for all 67Ga-labelled peptides. Internalisation into HEK-sst3 was usually faster for the 111In-labelled peptides. No internalisation was found into sst5. Biodistribution studies employing [67Ga-DOTA,1-Nal3]octreotide in comparison to [111In-DOTA,1-Nal3]octreotide and [67Ga-DOTA,Tyr3]octreotide showed a significantly higher and receptor-mediated uptake of the two 67Ga-labelled peptides in the tumour and somatostatin receptor-positive tissues. A patient study illustrated the potential advantage of a broad receptor subtype profile radiopeptide over a high-affinity sst2-selective radiopeptide. Conclusion: This study demonstrates that 67/68Ga-DOTA-octapeptides show distinctly better preclinical, pharmacological performances than the 111In-labelled peptides, especially on sst2-expressing cells and the corresponding animal models. They may be excellent candidates for further development for clinical studie

The clinical value of [90Y-DOTA]-D-Phe1-Tyr3-octreotide (90Y-DOTATOC) in the treatment of neuroendocrine tumours: A clinical phase II study

Purpose: The aim of this phase II study was to evaluate the tumour response of neuroendocrine tumours to targeted irradiation with the radiolabelled somatostatin analogue 90Y-DOTATOC. In addition, the palliative effect of 90-Y-DO-TATOC treatment on the malignant carcinoid syndrome and tumour-associated pain was investigated. Patients and methods: Forty-one patients (mean age 53 years) with neuroendocrine gastroenteropancreatic and bronchial tumours were included. Eighty-two percent of the patients had therapy resistant and progressive disease. The treatment con sisted of four intravenous injections ofa total of 6000 MBq/m2 90Y-DOTATOC, administered at intervals of six weeks. Results:The overall response rate was 24%. For endocrine pancreatic tumours it was 36%. Complete remissions (CR) were found in 2% (1 of 41), partial remissions (PR) in 22% (9 of 41), minor response in 12% (5 of 41), stable disease (SD) in 49% (20 of4l) and progressive disease (PD) in 15% (6 of4l). The median follow up was 15 months (range 1 month to 36 months). The median duration of response has not been reached at 26 months. The two-year survival time was 76 ± 16%. Eighty-three percent of the patients suffering from the malignant carcinoid syndrome achieved a significant reduction of symptoms. The treatment was well tolerated. A reduction of pain score was observed in all patients (5 of 41) with morphine dependent tumour-associated pain. Side effects included grade LU (NCIGC) pancytopenia in 5%, and vomiting shortly after injection in 23%. No grade III—IV renal toxicity was observed. Conclusion: Targeted radiotherapy with 90Y-DOTATOC is a novel, well-tolerated treatment for neuroendocrine turnours with a remarkable objective response rate, survival time, and symptomatic respons

Targeted therapy in nuclear medicine—current status and future prospects

In recent years, a number of new developments in targeted therapies using radiolabeled compounds have emerged. New developments and insights in radioiodine treatment of thyroid cancer, treatment of lymphoma and solid tumors with radiolabeled monoclonal antibodies (mAbs), the developments in the application of radiolabeled small receptor-specific molecules such as meta-iodobenzylguanidine and peptides and the position of locoregional treatment in malignant involvement of the liver are reviewed. The introduction of recombinant human thyroid-stimulating hormone and the possibility to enhance iodine uptake with retinoids has changed the radioiodine treatment protocol of patients with thyroid cancer. Introduction of radiolabeled mAbs has provided additional treatment options in patients with malignant lymphoma, while a similar approach proves to be cumbersome in patients with solid tumors. With radiolabeled small molecules that target specific receptors on tumor cells, high radiation doses can be directed to tumors in patients with disseminated disease. Radiolabeled somatostatin derivatives for the treatment of neuroendocrine tumors are the role model for this approach. Locoregional treatment with radiopharmaceuticals of patients with hepatocellular carcinoma or metastases to the liver may be used in inoperable cases, but may also be of benefit in a neo-adjuvant or adjuvant setting. Significant developments in the application of targeted radionuclide therapy have taken place. New treatment modalities have been introduced in the clinic. The concept of combining therapeutic radiopharmaceuticals with other treatment modalities is more extensively explore

Neodymium-140 DOTA-LM3:Evaluation of an <i>In Vivo</i> Generator for PET with a Non-Internalizing Vector

140Nd (t1/2 = 3.4 days), owing to its short-lived positron emitting daughter 140Pr (t1/2 = 3.4 min), has promise as an in vivo generator for positron emission tomography (PET). However, the electron capture decay of 140Nd is chemically disruptive to macrocycle-based radiolabeling, meaning that an in vivo redistribution of the daughter 140Pr is expected before positron emission. The purpose of this study was to determine how the delayed positron from the de-labeled 140Pr affects preclinical imaging with 140Nd. To explore the effect, 140Nd was produced at CERN-ISOLDE, reacted with the somatostatin analogue, DOTA-LM3 (1,4,7,10- tetraazacyclododecane, 1,4,7- tri acetic acid, 10- acetamide N - p-Cl-Phecyclo(d-Cys-Tyr-d-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)d-Tyr-NH2) and injected into H727 xenograft bearing mice. Comparative pre- and post-mortem PET imaging at 16 h postinjection was used to quantify the in vivo redistribution of 140Pr following 140Nd decay. The somatostatin receptor-positive pancreas exhibited the highest tissue accumulation of 140Nd-DOTA-LM3 (13% ID/g at 16 h) coupled with the largest observed redistribution rate, where 56 ± 7% (n = 4, mean ± SD) of the in situ produced 140Pr washed out of the pancreas before decay. Contrastingly, the liver, spleen, and lungs acted as strong sink organs for free 140Pr3+. Based upon these results, we conclude that 140Nd imaging with a non-internalizing vector convolutes the biodistribution of the tracer with the accumulation pattern of free 140Pr. This redistribution phenomenon may show promise as a probe of the cellular interaction with the vector, such as in determining tissue dependent internalization behavior

Production of Medical Radioisotopes with High Specific Activity in Photonuclear Reactions with γ\gamma Beams of High Intensity and Large Brilliance

We study the production of radioisotopes for nuclear medicine in $(\gamma,x{\rm n}+y{\rm p})$ photonuclear reactions or ($\gamma,\gamma'$) photoexcitation reactions with high flux [($10^{13}-10^{15}$)$\gamma$/s], small diameter $\sim (100 \, \mu$m$)^2$ and small band width ($\Delta E/E \approx 10^{-3}-10^{-4}$) $\gamma$ beams produced by Compton back-scattering of laser light from relativistic brilliant electron beams. We compare them to (ion,$x$n$+ y$p) reactions with (ion=p,d,$\alpha$) from particle accelerators like cyclotrons and (n,$\gamma$) or (n,f) reactions from nuclear reactors. For photonuclear reactions with a narrow $\gamma$ beam the energy deposition in the target can be managed by using a stack of thin target foils or wires, hence avoiding direct stopping of the Compton and pair electrons (positrons). $(\gamma,\gamma')$ isomer production via specially selected $\gamma$ cascades allows to produce high specific activity in multiple excitations, where no back-pumping of the isomer to the ground state occurs. We discuss in detail many specific radioisotopes for diagnostics and therapy applications. Photonuclear reactions with $\gamma$ beams allow to produce certain radioisotopes, e.g. $^{47}$Sc, $^{44}$Ti, $^{67}$Cu, $^{103}$Pd, $^{117m}$Sn, $^{169}$Er, $^{195m}$Pt or $^{225}$Ac, with higher specific activity and/or more economically than with classical methods. This will open the way for completely new clinical applications of radioisotopes. For example $^{195m}$Pt could be used to verify the patient's response to chemotherapy with platinum compounds before a complete treatment is performed. Also innovative isotopes like $^{47}$Sc, $^{67}$Cu and $^{225}$Ac could be produced for the first time in sufficient quantities for large-scale application in targeted radionuclide therapy.Comment: submitted to Appl. Phys.

Radiolabeled CCK/gastrin peptides for imaging and therapy of CCK2 receptor-expressing tumors

Cholecystokinin (CCK) receptors are overexpressed in numerous human cancers, like medullary thyroid carcinomas, small cell lung cancers and stromal ovarian cancers. The specific receptor-binding property of the endogenous ligands for these receptors can be exploited by labeling peptides with a radionuclide and using these as carriers to guide the radioactivity to the tissues that express the receptors. In this way, tumors can be visualized using positron emission tomography and single photon emission computed tomography imaging. A variety of radiolabeled CCK/gastrin-related peptides has been synthesized and characterized for imaging. All peptides have the C-terminal CCK receptor-binding tetrapeptide sequence Trp-Met-Asp-Phe-NH2 in common or derivatives thereof. This review focuses on the development and application of radiolabeled CCK/gastrin peptides for radionuclide imaging and radionuclide therapy of tumors expressing CCK receptors. We discuss both preclinical studies as well as clinical studies with CCK and gastrin peptides

Radiolabelled peptides for oncological diagnosis

Radiolabelled receptor-binding peptides targeting receptors (over)expressed on tumour cells are widely under investigation for tumour diagnosis and therapy. The concept of using radiolabelled receptor-binding peptides to target receptor-expressing tissues in vivo has stimulated a large body of research in nuclear medicine. The 111In-labelled somatostatin analogue octreotide (OctreoScan™) is the most successful radiopeptide for tumour imaging, and was the first to be approved for diagnostic use. Based on the success of these studies, other receptor-targeting peptides such as cholecystokinin/gastrin analogues, glucagon-like peptide-1, bombesin (BN), chemokine receptor CXCR4 targeting peptides, and RGD peptides are currently under development or undergoing clinical trials. In this review, we discuss some of these peptides and their analogues, with regard to their potential for radionuclide imaging of tumours

Imaging with non-FDG PET tracers: outlook for current clinical applications

Apart from the historical and clinical relevance of positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG), various other new tracers are gaining a remarkable place in functional imaging. Their contribution to clinical decision-making is irreplaceable in several disciplines. In this brief review we aimed to describe the main non-FDG PET tracers based on their clinical relevance and application for patient care

A comprehensive overview of radioguided surgery using gamma detection probe technology

The concept of radioguided surgery, which was first developed some 60 years ago, involves the use of a radiation detection probe system for the intraoperative detection of radionuclides. The use of gamma detection probe technology in radioguided surgery has tremendously expanded and has evolved into what is now considered an established discipline within the practice of surgery, revolutionizing the surgical management of many malignancies, including breast cancer, melanoma, and colorectal cancer, as well as the surgical management of parathyroid disease. The impact of radioguided surgery on the surgical management of cancer patients includes providing vital and real-time information to the surgeon regarding the location and extent of disease, as well as regarding the assessment of surgical resection margins. Additionally, it has allowed the surgeon to minimize the surgical invasiveness of many diagnostic and therapeutic procedures, while still maintaining maximum benefit to the cancer patient. In the current review, we have attempted to comprehensively evaluate the history, technical aspects, and clinical applications of radioguided surgery using gamma detection probe technology