Current Radiopharmaceuticals - Volume 3, Issue 4, 2010

Primary hyperparathyroidism (HPT) occurs in approximately 42 out of every 100,000 individuals, with women affected nearly three times more than men. It is predominantly caused by a single parathyroid adenoma, but can also be caused by glandular hyperplasia, and carcinoma. Definitive treatment for primary hyperparathyroidism remains surgical removal of affected glands, often a challenge due to the considerable anatomical variability. Minimally invasive radioguided parathyroidectomy (MIRP) is a directed surgical approach, made possible by the introduction of novel imaging techniques. Detection and precise localization of adenoma has been achieved by the use of sestamibi scans for a decade prior to the advent of computed tomography-(99m)Tc-sestamibi-single photon emission computed tomography image fusion (CT-MIBI-SPECT). In this paper, we present the use of CT-MIBI-SPECT fusion imaging in combination with a gamma probe intra-operatively as an accurate method for guided parathyroidectomy and discuss effects of the development of nuclear imaging techniques on radioguided parathyroid surgery.

Cyclo-(3-methylsaligenyl)-5-O-[1-(2,4-difluoro-5-[125I]iodophenyl)-2-deoxy-β-D-ribofuranosyl]phosphate (cycloSal- dRF[125I]IB) was radioiodinated with sodium [125I]iodide via copper-catalyzed isotope exchange in 48% radiochemical yield. cycloSal-dRF[125I]IB was found to be incorporated into the cytoplasmic nucleic acid and mitochondrial fractions of murine KBALB and K-STK (engineered to express HSV-1 thymidine kinase) cells in cell culture. Uptake was greater than that for either the corresponding nucleoside dRF[125I]IB or [125I]IUdR. These in vitro studies support a mechanism of metabolic activation to the free nucleotide, thereby effecting TK-bypass. Pharmacokinetic studies in rats reflect a complex interplay of tissue depot effects, hepatobiliary recycling, and metabolism. Biodistribution studies in tumor- bearing mice provide further evidence for lipophilic depot effects and hepatobiliary recirculation, with no evidence for active (metabolic) accumulation in any tissue.

Aim of the present review is to report the use of Positron Emission Tomography (PET) with [11C]- metahydroxyephedrine ([11C]mHED) in different clinical conditions, including heart failure, coronary artery disease, arrhythmogenic disorders, diabetes mellitus, idiopathic Parkinson's disease and adrenal tumors. [11C]mHED is a radio-labeled neurotransmitter PET tracer used to evaluate global and regional sympathetic presynaptic innervation in vivo, and firstly carried out in cardiac tissue in the 1990s. After the radiosynthesis and the injection of 740MBq of [11C]mHED with 2±0.5 Ci/μmole specific activity, the tracer is avidly retained in myocardium within 10 minutes and remains entrapped for at least 60 minutes. The transplanted heart is a good model to evaluate specificity of tracers for presynaptic innervation whose involvement in heart failure has been characterized in several studies using PET and [11C]mHED. In addition to transplanted heart, PET and [11C]mHED prognostic value has been also assessed in Diabetes Mellitus cardiac neuropathy and in neurological disorders related to Idiopathic Parkinson's disease. Neuronal imaging by PET may be also useful in determining the risk of sudden death in patients with viable but denervated myocardium after an infarction. In addition to the evaluation of neuronal cardiac disorders, PET with [11C]mHED has been proposed in oncological studies for the detection of adrenal tumors.

Full text Available.

Hepatic arterial infusion chemotherapy (HAIC) is a palliative therapy option for advanced, unresectable liver metastases from colorectal carcinoma. A woman with multiple colorectal liver metastases was treated with HAIC and systemic chemotherapy. Serial 18F-FDG PET/CT imaging showed local therapeutic response of liver metastases to regional delivery of chemotherapy, but concurrent disease progression at extra-hepatic sites suggesting ineffective systemic chemotherapy. Hepatic disease also progressed in the caudate lobe, likely due to variable regional arterial supply. This case is illustrative of the rationale for HAIC in the management of inoperable hepatic metastases and also demonstrates limitations of this approach.

Infarct avid radiopharmaceuticals are necessary for rapid and timely diagnosis of acute myocardial infarction. None of the infarct avid radiopharmaceuticals so far developed fulfill all the required criteria like rapid localization at the infarct, high avidity and specificity, and reasonable duration of scan positivity. 99mTc Cysteine was already reported from this laboratory as a suitable radiopharmaceutical to determine both morphology and function of kidney. The chemical structure of this radiopharmaceutical was also established. The present study demonstrates the affinity of the same chelate for damaged myocardial mass. 99mTc-cysteine was first tested on isoproterenol induced damaged rat myocardium, when ECG and histological studies demonstrated significant damage of the heart muscle following isoproterenol injection. The results were compared to that of 99mTc-glucarate. The uptake of 99mTc-cysteine in damaged rat myocardium was maximum (0.45% ID/g) when the animals were treated with isoproterenol 18 hrs before radiopharmaceutical injection; under the same experimental protocol 99mTc glucarate exhibited maximum heart uptake (0.263% ID/g) when injected 8 hrs after isoproterenol treatment. Evaluation was also performed on rat models of reperfused and non reperfused acute myocardial infarction. Animals were sacrificed after radiopharmaceutical injection and the excised hearts were subjected to radionuclide imaging, TTC and H-E staining. 99mTc-Cysteine chelate localized predominantly in the damaged portion. The highest infarct/viable tissue activity ratio (12/1) was obtained in 90 min occlusion model (protocol-2).

Purpose: Practically all solid malignant tumours have central hypoxia, which makes them less vulnerable to most forms of both radiotherapy and chemotherapy. Estramustine phosphate (EMP) is known to sensitise cancer cells and tumours to irradiation and to increase blood flow in malignant tumours. This study was designed to assess the effect of EMP and radiotherapy on the oxygenation status of the tumours. Methods and Materials: Nude mice with DU 145 human prostate cancer cell tumours were divided into four groups: group ER was treated with EMP 0.2 mg/d and external irradiation 3 × 6 Gy; group E received EMP, group R irradiation only; and group O no treatment. The degree of hypoxia in the tumours before and after treatment was measured using 18F-labelled fluoromisonidazole ([18F]FMISO) as a marker. The testis served as a control organ. Histological samples were studied for necrosis and proliferation (DAPI-stain for mitoses and Ki-67). Results: The tumours showed more [18F]FMISO uptake, indicating more hypoxia, than the testes in all four groups. EMP did not improve tumour oxygenation but enhanced the ability of radiotherapy to cause tumour necrosis. Conclusions: The angiogenic effect of EMP, if present, is not crucial in the mechanism of radiosensitation.

Nuclear Medicine and with it, the production of radiopharmaceuticals, represent an increasingly important part of the global medical market. This market is estimated at over $3 billion per year and growing. In this study, we compare the current Brazilian radiopharmaceuticals production and consumption with that of the USA and Europe. Brazil's market corresponds to 6.7% of the USA and Europe markets in terms of billing. While local demand for nuclear medicine procedures is increasing in Brazil, the number of facilities producing radiopharmaceuticals is quite small compared to other countries (2 : >30 : >100 facilities in Brazil, USA, and Europe, respectively). Current production capacity is inadequate to meet the growing demand. Rectifying Brazil's national policies to permit international competition in the production of radiopharmaceuticals would allow an increase in the capacity and the sustainability of the Nuclear Medicine and the radiopharmaceutical industry in Brazil.

ErbB-2 is a type 1 receptor tyrosine kinase over-expressed on ~30% of breast cancers and is an attractive target for the development of new diagnostic and therapeutic agents. In this study, an ErbB-2-targeting peptide, KCCYSL, previously isolated using bacteriophage display, was radiolabeled with [99mTc(H2O)3(CO)3]+ and examined for breast cancer in vitro cell binding and in vivo biodistribution and breast cancer imaging propensities. KCCYSL peptide was synthesized with the chelates diaminopropionc acid (DAP), Nα-histidinyl acetic acid [(NαHis)Ac], and 4-Ala-1,2-3-Triazol-1-acetic acid [(Ala-Triazol)Ac] at its amino-terminus via a gly-ser-gly (GSG) spacer and radiolabeled with [99mTc(H2O)3(CO)3]+. Radiolabeled peptide binding to cultured human MDA-MB-435 breast carcinoma cells was examined. Biodistribution and single photon emission computed tomography (SPECT)/CT imaging of the radiolabeled peptides were evaluated in female SCID mice bearing human MDA-MB-435 breast tumors. Results demonstrated that 99mTc(CO)3-DAP-GSG-KCCYSL, 99mTc(CO)3-(NαHis)Ac-GSG-KCCYSL and 99mTc(CO)3- (Ala-Triazol)Ac-GSG-KCCYSL were stable and bound to MDA-MB-435 cells. In vivo biodistribution studies revealed that tumor uptake of 99mTc(CO)3-DAP-GSG-KCCYSL was 1.67 ±0.16, 1.25 ±0.61, 0.88 ±0.12, 0.30 ±0.06 % ID/g at 1, 2, 4, and 24 h post injection, respectively. Tumor uptake of 99mTc(CO)3-(NαHis)Ac-GSG-KCCYSL was 0.76 ±0.13, 0.75 ±0.40, 0.33 ±0.08, 0.16 ±0.02 % ID/g at 1, 2, 4, and 24 h post injection, respectively. Tumor uptake of 99mTc(CO)3-(Ala- Triazol)Ac-GSG-KCCYSL was 1.15 ±0.12, 0.63 ±0.09, 0.30 ±0.02, 0.09 ±0.02 % ID/g at 1, 2, 4, and 24 h post injection, respectively. SPECT/CT studies showed tumor selective uptake of the peptides in the tumor-bearing mice. Specific uptake was confirmed by competitive receptor blocking studies. 99mTc(CO)3-DAP-GSG-KCCYSL and 99mTc(CO)3-(Ala-Triazol)Ac-GSG-KCCYSL may be better as imaging agents due to their higher tumor to non-target uptake ratios than 99mTc(CO)3-(NαHis)Ac-GSG-KCCYSL.

Third generation self-inactivating lentiviral vectors (LV) are highly efficient, achieving long-term expression of the transgene in several target tissues. In order to induce iodide and astatide uptake for radionuclide therapy, we employed LV co-expressing the sodium/iodide symporter (NIS) and GFP to transduce glioma cells (DBTRG). LV transduction was compared with transient or stably transfected cells. NIS-cDNA (2023bp) was inserted into the backbone vector plasmid pRRLsin.cPPT.CMV.MCS.iresGFP. Virus was produced in 293T using the packaging plasmids pMDLg/pRRE plus pRSV-Rev and the VSV-G envelope-encoding plasmid pMD.G. Transient transfection was performed with Fugene6. Frequency of GFP+ cells was quantified by cell sorter (FACS) and microscopy. NIS expression was examined by immunohistochemistry, iodine and astatine (At, a NISdependent alpha-particle emitting radionuclide) uptake ±perchlorate as specific NIS blocker. Stably NIS-expressing cells were geneticin-selected as positive controls. Experimental therapy measured by clonogenic assay was done using 10/100kBq/ml At-211. Quantification of viral transduction showed GFP-expression in up to 99.9% of the glioma cells and was clearly higher compared to transient transfection. Mean iodine uptake of transduced cells was 2396cpm/micro gram protein (vs. 2474cpm positive control) and significantly higher than that of transiently transfected cells (469cpm). Iodine uptake was specifically blocked with perchlorate >98% and negative in untransduced controls. At-211 treatment of transduced cells resulted in a specific cell kill. Robust LV transduction of NIS into target cells resulted in highly stable gene expression and functional activity. Our data suggest that lentiviral vectors are useful tools for NIS gene therapy approaches in combination with alpha or beta emitters.