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

A comparison of 111In-DOTATOC and 111In-DOTATATE: biodistribution and dosimetry in the same patients with metastatic neuroendocrine tumours

[Yttrium-90-DOTA-Tyr3]-octreotide (DOTATOC) and [177Lu-DOTA-Tyr3-Thr8]-octreotide (DOTATATE) are used for peptide receptor-mediated radionuclide therapy (PRMRT) in neuroendocrine tumours. No human data comparing these two compounds are available so far. We used 111In as a surrogate for 90Y and 177Lu and examined whether one of the 111In-labelled peptides had a more favourable biodistribution in patients with neuroendocrine tumours. Special emphasis was given to kidney uptake and tumour-to-kidney ratio since kidney toxicity is usually the dose-limiting factor. Five patients with metastatic neuroendocrine tumours were injected with 222MBq 111In-DOTATOC and 111In-DOTATATE within 2 weeks. Up to 48h after injection, whole-body scans were performed and blood and urine samples were collected. The mean absorbed dose was calculated for tumours, kidney, liver, spleen and bone marrow. In all cases 111In-DOTATATE showed a higher uptake (%IA) in kidney and liver. The amount of 111In-DOTATOC excreted into the urine was significantly higher than for 111In-DOTATATE. The mean absorbed dose to the red marrow was nearly identical. 111In-DOTATOC showed a higher tumour-to-kidney absorbed dose ratio in seven of nine evaluated tumours. The variability of the tumour-to-kidney ratio was high and the significance level in favour of 111In-DOTATOC was P=0.065. In five patients the pharmacokinetics of 111In-DOTATOC and 111In-DOTATATE was found to be comparable. The two peptides appear to be nearly equivalent for PRMRT in neuroendocrine tumours, with minor advantages for 111In/90Y-DOTATOC; on this basis, we shall continue to use 90Y-DOTATOC for PRMRT in patients with metastatic neuroendocrine tumour

DOTATOC: A powerful new tool for receptor-mediated radionuclide therapy

This study presents the first successful use of a peptidic vector, DOTATOC, labelled with the β-emitting radioisotope yttrium-90, for the treatment of a patient with somatostatin receptor-positive abdominal metastases of a neuroendocrine carcinoma of unknown localization. Tumour response and symptomatic relief were achieved. In addition, the new substance DOTA-TOC was labelled with the diagnostic chemical analogue indium-111 and studied in three patients with histopathologically verified neuroendocrine abdominal tumours for its diagnostic sensitivity and compared with the commercially available OctreoScan. In all patients the kidney-to-tumour uptake ratio (in counts per pixel) was on average 1.9-fold lower with111In-DOTATOC than with OctreoScan. DOTATOC could be a potential new diagnostic and therapeutic agent in the management of neuroendocrine tumour

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.

Somatostatin-based radiopeptide therapy with [177Lu-DOTA]-TOC versus [90Y-DOTA]-TOC in neuroendocrine tumours

Purpose: Somatostatin-based radiopeptide treatment is generally performed using the β-emitting radionuclides 90Y or 177Lu. The present study aimed at comparing benefits and harms of both therapeutic approaches. Methods: In a comparative cohort study, patients with advanced neuroendocrine tumours underwent repeated cycles of [90Y-DOTA]-TOC or [177Lu-DOTA]-TOC until progression of disease or permanent adverse events. Multivariable Cox regression and competing risks regression were employed to examine predictors of survival and adverse events for both treatment groups. Results: Overall, 910 patients underwent 1,804cycles of [90Y-DOTA]-TOC and 141 patients underwent 259cycles of [177Lu-DOTA]-TOC. The median survival after [177Lu-DOTA]-TOC and after [90Y-DOTA]-TOC was comparable (45.5months versus 35.9months, hazard ratio 0.91, 95% confidence interval 0.63-1.30, p = 0.49). Subgroup analyses revealed a significantly longer survival for [177Lu-DOTA]-TOC over [90Y-DOTA]-TOC in patients with low tumour uptake, solitary lesions and extra-hepatic lesions. The rate of severe transient haematotoxicities was lower after [177Lu-DOTA]-TOC treatment (1.4 vs 10.1%, p = 0.001), while the rate of severe permanent renal toxicities was similar in both treatment groups (9.2 vs 7.8%, p = 0.32). Conclusion: The present results revealed no difference in median overall survival after [177Lu-DOTA]-TOC and [90Y-DOTA]-TOC. Furthermore, [177Lu-DOTA]-TOC was less haematotoxic than [90Y-DOTA]-TOC

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