Preclinical studies of [68]Ga-DOTATOC: biodistribution assessment in Syrian rats and evaluation of absorbed dose in human organs

Objective[s]: Gallium-68 DOTA-DPhe[1]-Tyr[3]-Octreotide [[68]Ga-DOTATOC] has been applied by several European centers for the treatment of a variety of human malignancies. Nevertheless, definitive dosimetric data are yet unavailable. According to the Society of Nuclear Medicine and Molecular Imaging, researchers are investigating the safety and efficacy of this radiotracer to meet Food and Drug Administration requirements. The aim of this study was to introduce the optimized procedure for [68]Ga-DOTATOC preparation, using a novel germanium-68 [[68]Ge]/[68]Ga generator in Iran and evaluate the absorbed doses in numerous organs with high accuracy

Methods: The optimized conditions for preparing the radiolabeled complex were determined via several experiments by changing the ligand concentration, pH, temperature and incubation time. Radiochemical purity of the complex was assessed, using high-performance liquid chromatography and instant thin-layer chromatography. The absorbed dose of human organs was evaluated, based on biodistribution studies on Syrian rats via Radiation Absorbed Dose Assessment Resource Method

Results: [68]Ga-DOTATOC was prepared with radiochemical purity of >98% and specific activity of 39.6 MBq/nmol. The complex demonstrated great stability at room temperature and in human serum at 37[degree]C at least two hours after preparation. Significant uptake was observed in somatostatin receptor-positive tissues such as pancreatic and adrenal tissues [12.83%ID/g and 0.91%ID/g, respectively]. Dose estimations in human organs showed that the pancreas, kidneys and adrenal glands received the maximum absorbed doses [0.105, 0.074 and 0.010 mGy/MBq, respectively]. Also, the effective absorbed dose was estimated at 0.026 mSv/MBq for [68]Ga-DOTATOC

Conclusion: The obtained results showed that [68]Ga-DOTATOC can be considered as an effective agent for clinical PET imaging in Iran

In vivo measurement and characterization of a novel formulation of [[177]Lu]-DOTA-octreotate

Objective[s]: Lutetium-177 can be made with high specific activity and with no other isotopes of lutetium present, referred to as "No Carrier Added" [NCA] [177]Lu. We have radiolabelled DOTA-conjugated peptide DOTA-[Tyr[3]]-octreotate with NCA 177Lu ["NCA-LuTATE"] and used it in nearly 40 therapeutic administrations for subjects with neuroendocrine tumours or meningiomas. In this paper, we report on our initial studies on aspects of the biodistribution and dosimetry of NCA-LuTATE from gamma camera 2D whole body [WB] and quantitative 3D SPECT [qSPECT] [177]Lu imaging

Methods: Thirteen patients received 39 NCA-LuTATE injections. Extensive WB planar and qSPECT imaging was acquired at approximately 0.5, 4, 24 and 96 h to permit estimates of clearance and radiation dose estimation using MIRD-based methodology [OLINDA-EXM]

Results: The average amount of NCA-Lutate administered per cycle was 7839 +/- 520 MBq. Bi-exponential modelling of whole body clearance showed half lives for the fast and slow components of t[1/2]=2.1 +/- 0.6 h and t[1/2]=58.1 +/- 6.6 h respectively. The average effective dose to kidneys was 3.1 +/- 1.0 Gy per cycle. In eight patients completing all treatment cycles the average total dose to kidneys was 11.7 +/- 3.6 Gy

Conclusions: We have shown that NCA-LuTATE has an acceptable radiation safety profile and is a suitable alternative to Carrier-Added [177]Lu formulations. The fast component of the radiopharmaceutical clearance was closely correlated with baseline renal glomerular filtration rate, and this had an impact on radiation dose to the kidneys. In addition, it has less radioactive waste issues and requires less peptide per treatment

Gammagrafía con receptores de somatostatina en un caso de carcinoma medular de tiroides / Somatostatin receptor scintigraphy for thyroid medullary carcinoma: a case report

La gammagrafía con radiotrazadores que tienen afinidad por los receptores de somatostatina se ha convertido en metodología eficaz para el diagnóstico y estadificación de los tumores neuroendocrinos. Se presenta un caso en el cual el procedimiento radioisotópico muestra su efectividad en la localización del tumor primario.

Somatostatin receptor scintigraphy has become an important tool for diagnosis and evaluation of neuroendocrine tumors. This case report shows about the importance of the radionuclide procedure for the localization of the primary tumor.

Tratamiento de tumores neuroendocrinos (TNE) con péptidos análogos de la somatostatina marcados con radionucleidos / Treatment of neuroendocrine tumors (NET) with radiolabelled somatostatin analogues

Propósito. Los TNE avanzados tienen escasa respuesta a radioterapia o quimioterapia, el tratamiento sistémico con análogos de la SST radiactivos es una herramienta promisoria en su tratamiento. Presentamos nuestra experiencia, pionera en Latinoamérica, utilizando análogos de SST marcados con 90Y ó 177Lu. Material. Evaluamos 40 pacientes (50.3 años, rango 12-74) con TNE confirmados histológicamente y sobre-expresión de receptores de SST demostrada mediante imágenes. SPECT (111In-DOTATOC) ó PET/CT (68Ga-DOTATATE). Se evaluó respuesta clínica, laboratorio, imágenes con 111In-DOTATATE, post-terapia con 90Y ó 177Lu, 68Ga-DOTATATE PET/CT o TAC. Resultados. Observamos progresión de enfermedad en 10 (25.0 por ciento), remisión parcial en 25 (62.5 por ciento), enfermedad estable en 3 (7.5 por ciento) y remisión completa en 2 (5.0 por ciento). Hubo escasa toxicidad sin deterioro renal significativo. Observamos reducción tumoral y mejoría de calidad de vida en la mayoría de los pacientes. Conclusión. La terapia con radiopéptidos es un procedimento seguro y efectivo en el tratamiento de TNE avanzados.

Purpose. Advanced NETs have little response to radiotherapy or chemotherapy, systemic treatment with radioactive SST analogous is a promissory tool in its treatment. We present our pioneering experience in Latin America using analogous of SST labeled either with 90Y or 177Lu. Materials. We evaluated 40 patients (50.3 years, range 12-74) with histological proved NET and SST receptors over-expression demonstrated by SPECT or PET/CT images with 111In-DOTATOC or 68Ga-DOTATATE. We evaluated clinical response, laboratory test, images with 111In-DOTATATE, 90Y, 177Lu, and 68Ga-DOTATATE PET/CT or CT. Results. We observed progression of disease in 10 (7,5 percent), partial remission in 25 (62,5 percent), stable disease in 3 (7,5 percent) and complete remission in 2 (5,0 percent). There was little toxicity without significant renal deterioration. We observed tumor mass reduction and improvement of quality of life in most of the patients. Conclusion. The therapy with radiopeptides is a safe and effective procedure in the treatment of advanced NET.

Role of (68)Ga-DOTATOC PET/CT in the Evaluation of Primary Pulmonary Carcinoids

BACKGROUND/AIMS: Although carcinoid tumors usually have good prognosis, early and specific diagnosis is important. Computed tomography and magnetic resonance imaging do not provide findings that are specific for carcinoids, and somatostatin receptor scintigraphy suffers from low spatial resolution. 18-Fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) has limited sensitivity for carcinoids due to low uptake of the marker. A PET/CT system that uses the somatostatin receptor-based PET tracer 1,4,7,10-tetraazacyclododecane-N(I),N(II),N(III),N(IIII)-tetraacetic acid (D)-Phe(1)-thy(3)-octreotide ((68)Ga-DOTATOC) has also been used in the evaluation of carcinoids, although information regarding its use for the detection of primary pulmonary carcinoids is limited. Thus, we investigated the value of (68)Ga-DOTATOC PET/CT for the diagnosis of primary pulmonary carcinoid tumors. METHODS: This was a retrospective analysis of patients with primary pulmonary tumors who underwent (68)Ga-DOTATOC PET/CT. All the patients had a histopathologic diagnosis of carcinoid. The rate of detection of primary pulmonary carcinoid tumors using (68)Ga-DOTATOC PET/CT was assessed. RESULTS: Twenty patients were diagnosed as having carcinoid, and 19 tumors showed significant uptake on (68)Ga-DOTATOC (detection rate, 95%). The maximal standardized uptake value (SUV(max)) ranged from 1.1 to 66, with a median value of 21.6. In one patient, (68)Ga-DOTATOC PET/CT revealed additional lesions. CONCLUSIONS: Our results demonstrate that (68)Ga-DOTATOC PET/CT is useful in the evaluation of primary pulmonary carcinoids and should be included in the diagnostic work-up of these patients.

Synthesis, development and preclinical comparison of two new peptide based freeze-dried kit formulation 99mTc-EDDA-Tricine-HYNIC-TOC and 99mTc-EDDA-Trinice-HYNIC-TATE for somatostatin receptor positive tumor scintigraphy

Somatostatin receptor [sstr] scintigraphy with [111In diethylenetriaminepentaacetic acid]-octreotide [[111In-DTPA]-OC] has became a routine diagnostic procedure in oncology. However, it suffers from some drawbacks concerning the limited availability, suboptimal imaging properties and elevated radiation burden of 111In. In this study synthesis, conjugation and preclinical evaluation of two new freeze-dried kit formulation based on somatostatin analogues, Tyr3-Octreotide [TOC] and Tyr3-octreotate [TATE], designed for the labeling with 99mTc are described. After cleavage from the resin and preparation of the cyclized peptides, these compounds were conjugated with 6-hydrazinopyridine-3-carboxylic acid [HYNIC] in solution. Radiolabeling of HYNIC peptide conjugates was performed at high specific activity using one-step kits formulation based on tricine and ethylenediamine-N,N? -diacetic acid [EDDA] as co-ligands. Both, 6-hydrazinopyridine-3-carboxylic acid0-Tyr3-Octreotide [HYNIC-TOC] and 6-hydrazinopyridine-3-carboxylic acid0-Tyr3-Octreotate [HYNIC-TATE], showed a specific and high rate of internalization after 4 h in AR4-2J rat pancreatic tumor cells, [11.2 +/- 0.8 and 18.1 +/- 1.2 respectively]. Biodistribution studies in AR4-2J tumor-bearing rats showed rapid clearance of both analogues from all sstr-negative tissues except the kidneys. The specific uptake in tumor and sstr-positive tissues especially pituitary, pancreas and adrenals were observed. After 4 h the adrenals to pancreas uptake ratio for HYNIC-TOC was higher than that of HYNIC-TATE. Although both compounds had high kidney and low liver excretion, for HYNIC-TATE, it was lower. The results suggest these two new peptide based freeze-dried kits might be of great promise for clinical application in imaging of somatostatin receptor-positive tumors

[Evaluation and comparison of different quality control methods in radiochemical purity determination of new peptide kits 99mTc-EDDA-Tricine-HYNIC-Tyr3-Octreotide and 99mTc-EDDA-Tricine-HYNIC-Tyr3-octreotate for imaging somatostatin receptor positive tumors]

Using labeled peptides enjoys high importance in nuclear medicine. Somatostatin analogs labeled with different radionuclide are vastly investigated for diagnosis or treatment of somatostatin receptor positive tumors. Labeling somatostatin analogs with 99mTc as alternative of 111In needs doing different quality control method for determination of labeling yield and complex stability for clinic applications. For determining radiochemical purity, three different methods were compared and evaluated including HPLC, TLC and Sep-Pak. All the three methods were suitable for determining of radiochemical purity in peptide kits, although using HPLC was more effective rather than the others. HPLC was the best method for determination of radiochemical purity of the peptide kits. TLC or Sep-Pak method should only be employed if HPLC is not available in nuclear medicine clinics, and after training and gaining sufficient operational experience. In this research, a new monoclonal antibody against colon cancer cells was prepared and antigen concentration in different cells determined by a radioimmunoassay method using iodine [I-125] labeled protein G. 125I-labeled protein G percent binding to white blood cell, HT29, LS180 and MCF7 cell lines were 7.1%, 91.2%, 75.8% and 40.2%, respectively. Regarding importance of monoclonal antibody applications, it is necessary to find an efficient method for their evaluation in cancer therapy. In this method, a radioactive agent with no count restriction was used. Also by this method, amount of the antigen can be easily quantified