Evaluating the potential of kit-based 68Ga-ubiquicidin formulation in diagnosis of infection: a pilot study68Ga.

OBJECTIVE: The aim was to evaluate the diagnostic potential of Ga-ubiquicidin positron-emission tomography/computed tomography (PET/CT) in imaging patients with infection. MATERIALS AND METHODS: Ga-NOTA-ubiquicidin (Ga-UBI) was prepared by addition of freshly eluted Ga-chloride from Ge/Ga generator into the NOTA-ubiquicidin vial and incubated at room for 15 min at 90°C. After compounding of the radiopharmaceutical, quality control using instant thin-layer chromatography, culture and endotoxin estimation was performed. Patients with suspected infection associated with diabetic foot, cellulitis and fracture were selected for the pilot study investigation to evaluate the ability of the tracer Ga-UBI in localization at infection sites. The PET/CT findings were compared with other diagnosis like microbial culture reports and bone scintigraphy to evaluate true positives or negatives in the study. RESULTS: The current study demonstrated the potential of kit-based Ga-UBI in localization of infection sites in most of the patients proven positive for infection on culture tests and bone scintigraphy. The kit could offer radiolabeling yield more than 95% in 15 min incubation at 90°C. Quality control rendered the kit as a clinical grade preparation with endotoxin content less than 10 EU/ml and sterility up to 14 days of culture incubation. Eight of 10 patients underwent culture test and showed positive results. Two patients had undergone three-phase bone scan as an indirect sign of active infection. Ga-UBI PET/CT showed tracer localization in four of eight culture-positive patients. Tracer localization was observed in one of two patients whose culture reports were not available. Ga-UBI failed to identify infection in four patients with culture-positive results. CONCLUSION: The present study concluded that Ga-UBI prepared using NOTA-UBI kit is a potential agent in targeting infections associated with disease conditions including diabetic foot, cellulitis and fracture. The patient selection holds significance in accurate diagnosis using Ga-UBI PET/CT.

Two Cases of 188Re Microspheres for Inoperable Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies. Often, patients present with inoperable and advanced disease. Selective internal radionuclide therapy offers prolonged survival and improved quality of life by delivering high radiation dose to the tumor with minimal complications. We report 2 inoperable cases of HCC treated with therapeutic dose of indigenously developed Re microspheres delivered to the hepatic lesions by transarterial catheterization. Follow-up CT revealed necrosis within the lesion, suggesting response to selective internal radionuclide therapy. Re microspheres may be a potential treatment option for inoperable HCC with or without portal vein thrombosis.

Concentration protocol of rhenium-188 perrhenate eluted from tungsten-188/rhenium-188 generator for the preparation of high-yield rhenium-188-labelled radiopharmaceuticals.

Rhenium-188 (Re) is a ß, γ emitter and considered a theranostic radionuclide. It is used for bone pain palliation, treatment of unresectable hepatocellular carcinoma, skin keloids, etc. Re perrhenate is eluted from a W/Re generator in large volumes (8-14 ml) of 0.9% normal saline. Concentrating Re to 1-2 ml volume is important for high radiolabelling yield of various Re radiopharmaceuticals, especially when the generator is old. For this, ion exchange column was prepared in-house, and Re was concentrated using silver ion exchange column and QMA cartridge. Re perrhenate eluted in saline was concentrated to 1 ml with more than 99% yield.

Multifarious Ga-68 Labeled PET Radiopharmaceuticals in Imaging Various Malignancies.

The gamut of gallium labeled radiopharmaceuticals contributes to augmented variety in molecular imaging approach for in vivo identification of tumor characteristics. The spectrum ranges from somatostatin receptor based target-specific imaging agents, to those used for tumor imaging based on specific receptor types extending into ones used for therapeutic monitoring. The versatility of gallium chemistry provides the needed advantage for imaging which is further exploited in clinical practice influences the specificity of tumor imaging. Ga-68 has revealed applicability in labeling compounds from nanoparticles to micro as well as macromolecules. We in this image, present variety of frequently and infrequently used gallium labeled radiopharmaceuticals, for imaging diverse malignancies other than conventional established tracers.

99mTc-TRODAT-1 SPECT/CT imaging as a complementary biomarker in the diagnosis of parkinsonian syndromes.

INTRODUCTION: Parkinson's disease (PD) and Parkinson plus syndromes (PPS) are neurodegenerative movement disorders caused by loss of dopamine in the basal ganglia. The diagnosis of both PD and PPS is complex as it is made solely on the basis of clinical features, with no established imaging modality to aid in the diagnosis. Technetium-99m-labeled tropane derivative (Tc-TRODAT-1) binds to the dopamine transporters present in the presynaptic membrane of the dopaminergic nerve terminal. The aim of this prospective study was to investigate the potential usefulness of Tc-TRODAT-1 imaging in the diagnosis of PD and PPS. PATIENTS AND METHODS: Fifty-eight patients with a clinical diagnosis of idiopathic PD or PPS were recruited. The severity of the disease was assessed using the Hoehn and Yahr scale. Patients in stage I and II were considered as cases of Early PD. Twenty-five apparently healthy volunteers served as controls. Brain single-photon emission computed tomography/computed tomography in all the participants was performed 3-4 h after an injection of Tc-TRODAT-1. Specific uptake ratios (SURs) of striatum were calculated for both the left and right striatum, and the values were compared between PD, PPS, and healthy volunteers. RESULTS: A significant lower uptake of tracer activity was found in either of the striatum in PD and PPS cases compared with the control group, which showed a symmetrical comma-shaped striatal uptake. This was also reflected in the SUR values, which were significantly higher in the control group in comparison with the PD and PPS patients (P<0.001). A significant difference was also found in the SUR values between the cases of early PD and control group (P<0.001).No significant difference was noted among the SUR values in different Hoehn and Yahr stages. CONCLUSION: For clinical practice, both the visual analysis and the quantitative parameters of Tc-TRODAT-1 single-photon emission computed tomography/computed tomography showed usefulness in distinguishing cases of PD and PPS from the healthy individuals.

In-house Preparation and Quality Control of Tc99m TRODAT 1 for Diagnostic Single-photon Emission Computed Tomography/Computed Tomography Imaging in Parkinson's Disease.

PURPOSE OF STUDY: Loss of dopamine neurons in the brain is a characteristic feature of Parkinson's disease (PD). TRODAT-1 is a tropane derivative that binds to dopamine transporter (DAT) receptors. It can be used for noninvasive in vivo imaging of DAT receptors leading to the early detection of PD. The present study aims to optimize the in-house radiolabeling of TRODAT-1 with Tc-99 m in hospital radiopharmacy set up along with performing single-photon emission computed tomography/computed tomography imaging in patients with PD. MATERIALS AND METHODS: Radiolabeling was performed through transchelation method. For optimization studies, varied amount of glucoheptonate (GHA) and stannous chloride was incubated with Tc-99 m for 10 min at room temperature. TRODAT-1 was added to the reaction mixture followed by incubation at 95°C for various time intervals. Phosphate buffer saline was added to maintain the pH of the final product. After performing the quality checks, whole-body imaging was performed to check the biodistribution in 4 patients at 1 h postinjection of 20-25 mCi (740-925 MBq) of Tc-99 m-TRODAT-1. Regional brain imaging was performed at 3-4 h. Clinical evaluation was done in control (n = 5) and in patients with PD (n = 5). RESULTS: Radiolabeling yield of 100% was achieved by incubating TRODAT-1 with Tc-99 m GHA. All the quality control indicated the suitability of radiopharmaceutical for the intravenous administration. Good uptake of Tc-99 m TRODAT-1 was observed in the striatum of normal patients. However, decreased uptake was seen in patients with PD. CONCLUSION: Tc-99 m TRODAT-1 is a potential radiopharmaceutical for the diagnosis and staging PD which can be radiolabeled in-house with good yield leading to its easy availability.

Noninvasive treatment of keloid using customized Re-188 skin patch.

Keloids are developed as fibrotic scar at the site of surgery or trauma and often enlarge beyond the original scar margins. Re-188 colloid coated customized patch was superficially fixed onto the lesion for 3 hrs. The same patch was reapplied on the lesion on third day for 3 hrs. The patients were followed up at 1, 3,6 and 12 months post treatment. The size and elevation of the keloid lesion was reduced after treatment. The total radiation dose from the patch (day-1 and day-3) was 100 Gy/mCi of Re-188. The radioactive patch treatment of keloids is noninvasive, painless and safe with prolonged outcome.

Usefulness of 68Ga-DOTA-RGD (αvß3) PET/CT Imaging in Thyroglobulin Elevation With Negative Iodine Scintigraphy.

TENIS (thyroglobulin elevation with negative iodine scintigraphy) syndrome in patients with differentiated thyroid carcinoma is not a rare finding. In such patients, F-FDG PET/CT can help in disease evaluation. RGD tripeptide, used for imaging angiogenesis, may also help in disease detection in patients with negative radioiodine whole-body scan. We present 1 such case in whom Ga-RGD tripeptide imaging was helpful in disease detection in the setting of negative radioiodine whole-body scan.

Development of Lu-177-trastuzumab for radioimmunotherapy of HER2 expressing breast cancer and its feasibility assessment in breast cancer patients.

HER2/neu is over expressed in 20-25% of breast cancers. HER2 breast cancers are aggressive and are associated with poor prognosis. The aim of this study was to develop the clinical grade Lu-177-trastuzumab and its preliminary evaluation for specific tumor targeting in HER2 positive breast cancer patients. Trastuzumab was conjugated to bifunctional chelator, DOTA, and characterized for integrity and the number of molecules conjugated. Radiolabeling of DOTA-conjugated trastuzumab was optimized using Lu-177. Quality control parameters including radiochemical purity, stability, sterility, pyrogenicity and immunoreactivity were assessed. A preliminary pilot study was conducted on breast cancer patients (n = 6 HER2 positive and n = 4 HER2 negative) to evaluate the ability of Lu-177-trastuzumab for HER2 specific tumor targeting. The conjugates were efficiently labeled with Lu-177 with high radiochemical purity (up to 91%) and specific activity (6-13 µCi/µg). Lu-177-trastuzumab was stable up to 12 hr post labeling. The radioimmunoassay demonstrated good antigen binding ability and specificity for HER2 receptor protein. The patient studies showed the localization of Lu-177-trastuzumab at primary as well as metastatic sites (HER2 positive) in the planar and SPECT/CT images. No tracer uptake was observed in HER2 negative patients that indicated the specificity of Lu-177-trastuzumab. The study demonstrated that in-house developed Lu-177-trastuzumab has specific targeting ability for HER2 expressing lesions and may in future become a palliative treatment option in the form of targeted radionuclide therapy for disseminated HER2 positive breast cancer.

Detailed evaluation of different (68)Ge/(68)Ga generators: an attempt toward achieving efficient (68)Ga radiopharmacy.

The present study is aimed at carrying out a comparative performance evaluation of different types of (68)Ge/(68)Ga generators to identify the best choice for use in (68)Ga-radiopharmacy. Over the 1 year period of evaluation, the elution yields from the CeO2-based and SiO2-based (68)Ge/(68) Ga generators remained almost consistent, in contrast to the sharp decrease observed in the elution yields from TiO2 and SnO2-based generators. The level of (68)Ge impurity in (68)Ga eluates from the CeO2 and SiO2-based (68)Ge/(68)Ga generator was always <10(-3)%, while this level increased from 10(-3)% to 10(-1)% in case of TiO2 and SnO2-based generators. The level of chemical impurities in (68)Ga eluates from CeO2 and SiO2-based (68)Ge/(68)Ga generators was negligibly low (<0.1 ppm) in contrast to the significantly higher level (1-20 ppm) of such impurities in eluates from other two generators. As demonstrated by radiolabeling studies carried out using DOTA-coupled dimeric cyclic RGD peptide derivative (DOTA-RGD2), CeO2-PAN and SiO2-based generators are directly amenable for radiopharmaceutical preparation, whereas the other generators can be only used after post-elution purification of (68)Ga eluates. Clinically relevant dose of (68)Ga-DOTA-RGD2 was prepared in a hospital radiopharmacy for non-invasive visualization of tumors in breast cancer patients using positron emission tomography.

Toward realization of 'mix-and-use' approach in 68Ga radiopharmacy: preparation, evaluation and preliminary clinical utilization of 68Ga-labeled NODAGA-coupled RGD peptide derivative.

INTRODUCTION: The present article demonstrates a 'mix-and-use' approach for radiolabeling RGD peptide derivative with (68)Ga, which is easily adaptable in hospital radiopharmacy practice. The radiotracer thus formulated was successfully used for positron emission tomography (PET) imaging of breast cancer in human patients. METHODS: The conditions for radiolabeling NODAGA-coupled dimeric cyclic RGD peptide derivative [NODAGA-(RGD)2] with (68)Ga were optimized using (68)Ga obtained from a (68)Ge/(68)Ga generator developed in-house with CeO2-PAN composite sorbent as well as from a commercial (68)Ge/(68)Ga generator obtained from ITG, Germany. Preclinical studies were carried out in C57BL/6 mice bearing melanoma tumors. The radiotracer was prepared in a hospital radiopharmacy using (68)Ga obtained from ITG generator and used for monitoring breast cancer patients by positron emission tomography (PET) imaging. RESULTS: (68)Ga-NODAGA-(RGD)2 could be prepared with high radiolabeling yield (>98%) and specific activity (~50 GBq/µmol) within 10 min at room temperature by mixing (68)Ga with the solution of the peptide conjugate. In vivo biodistribution studies showed significant uptake (5.24±0.39% ID/g) in melanoma tumor at 30 min post-injection, with high tumor-to-background contrast. The integrin αvß3 specificity of the tracer was corroborated by blocking study. Preliminary clinical studies in locally advanced breast cancer (LABC) patients indicated specifically high tumor uptake (SUVmax 10-15) with good contrast. CONCLUSIONS: This is one of the very few reports which presents preliminary clinical data on use of (68)Ga-NODAGA-(RGD)2 and the developed 'mix-and-use' holds tremendous prospect in clinical PET imaging using (68)Ga.

Integrin αvß3 as a Promising Target to Image Neoangiogenesis Using In-House Generator-Produced Positron Emitter (68)Ga-Labeled DOTA-Arginine-Glycine-Aspartic Acid (RGD) Ligand.

For the growth and spread of a tumor beyond 2 mm, angiogenesis plays a crucial role, and association of various integrins with angiogenesis is evidential. The aim of the study was radiolabeling of DOTA-chelated RGD (arginine-glycine-aspartic acid) peptide with (68)Ga for PET imaging in locally advanced breast carcinoma. DOTA-RGD was incubated with (68)GaCl3, eluted in 0.05 m HCl. Elution volume, peptide amount, and reaction pH were studied. Radio-ITLC, gas chromatography, endotoxin, and sterility testing were performed. Serial (n=3) and whole-body (n=2) PET/CT imaging was done on patients post i.v. injection of 111-185 MBq of (68)Ga-DOTA-RGD. Maximum radiolabeling yield was achieved with 3 mL elution volume of 15-20 µg peptide at pH 3.5-4.0 with 10 minutes of incubation at 95°C. Product samples were sterile having 99.5% radiochemical purity with residual ethanol content and endotoxins in injectable limits. Intense radiotracer uptake was noticed in the tumor with SUVmax 15.3 at 45 minutes in serial images. Physiological radiotracer uptake was seen in the liver, spleen, ventricles, and thyroid with excretion through the kidneys. The authors concluded that (68)Ga-DOTA-RGD has the potential for imaging α,vß3 integrin-expressing tumors.

Quality control of positron emission tomography radiopharmaceuticals: An institutional experience.

PURPOSE OF THE STUDY: To study quality control parameters of routinely prepared positron emission tomography (PET) radiopharmaceuticals. MATERIALS AND METHODS: Three PET radiopharmaceuticals fluorine-18 fluorodeoxyglucose (F-18 FDG), N-13 ammonia (N-13 NH3), and Ga-68 DOTATATE (n = 25 each), prepared by standardized protocols were used. The radionuclide purity, radiochemical purity, residual solvents, pH, endotoxins, and sterility of these radiopharmaceuticals were determined. RESULTS: The physical half-life of radionuclide in radiopharmaceuticals, determined by both graphical and formula method, demonstrated purity of radionuclides used. pH of all PET radiopharmaceuticals used was in the range of 5-6.5. No microbial growth was observed in radiopharmaceutical preparations. The residual solvents, chemical impurity, and pyrogens were within the permissible limits. CONCLUSIONS: All three PET radiopharmaceuticals were safe for intravenous administration.