Current Radiopharmaceuticals - Volume 5, Issue 4, 2012

Stereotactic radiosurgery is an emerging treatment option offered to patients with Glioblastoma multiforme (GBM). Radiosurgery is performed as an outpatient procedure and provides a safe and effective non invasive treatment for focal GBM. High energy beams originating from cobalt sources placed into an helmet (Gamma-Knife) or generated by a linear accelerator (LINAC) rotating on a gantry (X-Knife, Novalis) or maneuvered by a robotic arm (CyberKnife) are delivered with submillimetric accuracy to a selected intracranial target. Treatment accuracy is provided by image-guided volumetric CT and MR studies complemented with advanced metabolic neuroimaging techniques such as CT-PET. Radiosurgery is typically used as a salvage treatment in patients with recurrent GBM to avoid further surgical procedures or as a complement to conventional fractionated radiotherapy. This paper reviews the emerging role of stereotactic radiosurgery in the treatment of GBM.

Despite the extensive research efforts over the past century, glioblastoma multiforme (GBM) remains an ominous diagnosis leading fast to progressive disability and death despite the aggressive treatment including microsurgical resection, chemotherapy, radiotherapy and stereotactic radiosurgery. Advanced neuroimaging techniques, such as volumetric acquisitions, spectroscopy, diffusion and perfusion studies added to conventional imaging, provide in selected cases a non-invasive alternative to pathological diagnosis but they are also precious tools to define the boundaries of image-guided microsurgical resection and/or radiosurgical ablation. This paper reviews the role of advanced neuroimaging techniques in the diagnosis and treatment of GBM.

Glioblastoma multiforme (GBM) is the most common and most malignant primary brain tumor occurring during adulthood. The incidence of GBM is nearly 5 cases per 100,000 population per year. The standard of care for newly diagnosed GBM includes surgical resection when possible, followed by radiotherapy and concomitant and adjuvant chemotherapy with temozolomide. Imaging modalities used in nuclear medicine, namely positron emission tomography (PET) and single-photon emission computed tomography (SPECT) have been employed towards the evaluation of brain tumors. Herewith, we discuss the value of the above imaging techniques in the assessment of GBM aggressiveness, in the distinction of treatment induced necrosis from glioma recurrence, in the estimation of overall prognosis and in the evaluation of treatment response in patients with GBM.

Morpholine-4-carboxylic acid {(S)-1-[4-cyano-1-(3-morpholin-4-yl-propyl)-piperidin-4-ylcarbamoyl]-4,4- dimethyl-hexyl}-amide, (1) is a potent reversible and selective cathepsin S inhibitor. Deuterium labeled (1) was prepared in four steps in 62% overall yield from [2H8]- morpholine and chiral acid (6). Carbon-14 labeled (1) was obtained in two steps using sodium [14C]-cyanide in a modified Strecker reaction followed by amide bond formation with acid (6) in 74% overall radiochemical yield. The phosphate salt of this compound was produced by treatment with phosphoric acid in methanol in 97% yield.

In this work Nimotuzumab (monoclonal antibody, recognizes the EGF-R) was radiolabeled with 177Lu as a potential cancer therapy radiopharmaceutical. In-vitro cell binding studies and in-vivo biodistribution and imaging studies were performed to determine the radiochemical stability, targeting specificity and pharmacokinetics of the 177Lu-labeled antibody. Nimotuzumab was derivatized with DOTA-NHS at room temperature for 2 hours. DOTA-Nimotuzumab was radiolabeled with 177LuCl3 (15 MBq/mg) at 37ºC for 1 h. The radiochemical purity was assessed by ITLC, silica gel and by RP-HPLC. Binding specificity studies were performed with EGF-R positive A431 human epithelial carcinoma and EGF-R negative MDA-MB-435 breast carcinoma cells. Biodistribution studies were performed in healthy female CD-1 mice at 1 h, 4 h, 24 h, and A431 xenografted nude mice at 10 min, 1 h, 4 h, 24 h, 48 h, and 96 h. SPECT-CT imaging studies were performed in A431 xenografted mice at 24 h post injection. DOTA-Nimotuzumab was efficiently labeled with 177LuCl3 at 37°C. The in vitro stability of labeled product was optimal over 24 h in buffered saline and mouse serum. Specific recognition of EGF-R by 177Lu-DOTA-Nimotuzumab was observed in A431 cell binding studies. Biodistribution studies demonstrated increasing tumor uptake of 177Lu-DOTA-Nimotuzumab over time, with tumor to muscle ratios of 6.26, 10.68, and 18.82 at 4 h, 24 h, and 96 h post injection. Imaging of A431 xenografted mice showed high uptake in the tumor. 177Lu-DOTA-Nimotuzumab has the potential to be a promising therapy agent, which may be useful in the treatment of patients with EGF-R positive cancer.

In last few years, the shortage of molybdenum-99 (99Mo) was felt in the developed and developing countries hospitals, where diagnostic nuclear medicine is practiced. To overcome the shortage of 99Mo various routes of its production by accelerators and reactors generating low and high specific activity products have been planned. High specific activity 99Mo obtained by fission of uranium-235 (235U) has completely dominated in the manufacturing of technetium-99m (99mTc) generators in last 3-4 decades, but due to proliferation and dirty bomb, issues non fission routes of 99Mo production are emphasized. Future of low specific activity 99Mo is discussed.

High-specific activity radiolabeled melanocortin peptide preparations are necessary for optimal melanoma imaging due to the relatively low number of melanocortin-1 receptors (MC1-Rs) per tumor cell. In this study, a one-step synthesis of 62Cu-labeled MC1-R targeting peptide Re(Arg11)CCMSH was developed, which yielded high specific activity radiolabeled peptide preparations that required no post-labeling purification. DOTA and NOTA conjugated Re(Arg11)CCMSH peptides were synthesized and examined for 62Cu radiolabeling and cell binding properties. Biodistribution and PET imaging studies were performed to assess the in vivo tumor targeting and imaging characteristics of the optimal radiolabeled peptide. Melanoma cell binding affinities for NOTA-, NOTA-GGG-, and NOTA-GSG- conjugated Re(Arg11)CCMSH were determined to be 1.3×10-9 M, 1.9×10-9 M and 6.0×10-9 M. The 62Cu radiolabeling efficiencies of DOTA- and NOTA- conjugated Re(Arg11)CCMSH analogs were 30% and >98% after 2 min at 24° C, while 0.5 μg of NOTA-GGG-peptide could be labeled to >95% with a maximum specific activity of 138 Ci/μmol. Tumor uptake of 62Cu- NOTA-GGG-Re(Arg11)CCMSH in B16/F1 melanoma bearing mice was 4.65±0.48% ID/g and 9.43±2.69% ID/g at 20 and 40 min post injection and was visualized by PET imaging. High specific activity 62Cu-NOTA-GGG-Re(Arg11)CCMSH was prepared in a one-step procedure at 24°C in 6 min. 62Cu-NOTA-GGG-Re(Arg11)CCMSH exhibited MC1-R selective binding and rapid tumor uptake in B16/F1 melanoma bearing mice that was confirmed by PET imaging studies. High specific activity 62Cu from a 62Zn/62Cu generator coupled with simple one step radiolabeling procedures makes 62Cu an attractive radionuclide for PET imaging of low-density receptor targets.

Nanotechnology has been the last frontier in the diagnoses and treatment of many diseases, especially in oncology. The use of nanoparticles of radiopharmaceuticals may represent the future of Nuclear Medicine. In this study we developed, characterized and tested polymeric nanoparticles of FMISO (fluoromisonidazole) in a dynamic study of biodistribution. The results of the development as characterization showed that nanoparticles were well obtained with a size range of 300- 500nm and a spherical shape.

Aim: Radiolabeled porphyrin derivatives could be envisaged as potential agents for targeted tumor therapy owing to the inherent tumor accumulation property exhibited by porphyrins. However, to achieve adequately high tumor accumulation and retention therein along with fast clearance from all non-target organs, an optimum balance between the hydrophilicity and lipophilicity must be achieved. Based on our prior experiences of working with 109Pd-labeled porphyrins with variable lipophilicity and hydrophilicity, we have envisioned a suitable porphyrin derivative which could be expected to have the required balance between lipophilicity and hydrophilicity when complexed with 109Pd. Towards this, 5,10,15,20- tetrakis[4-carboxymethyleneoxyphenyl]porphyrin (PHBEPH) was synthesized, radiolabeled with 109Pd and its biological behavior in small animal model was studied. Experimental: The porphyrin derivative was synthesized and characterized following the reported procedure and radiolabeled with 109Pd [E β(max) = 1.12 MeV, E γ = 88 keV (3.6%), T1/2 = 13.7 h], which was produced by the thermal neutron bombardment on enriched (98% in 108Pd) metallic Pd target at a flux of 3×1013 n/cm2.s for 3 d. Biological behavior of the radiolabeled agent was studied by biodistribution studies in Swiss mice bearing fibrosarcoma tumors. Results: 109Pd was produced with a specific activity of ∼1.85 GBq/mg (50 mCi/mg) and radionuclidic purity of 100%. 109Pd complex of the synthesized porphyrin derivative was prepared with excellent radiochemical purity (>98%) and the complex was observed to exhibit Log P value of -1.29. Biodistribution studies revealed good tumor uptake [(3.55±0.49)% injected activity (IA)/g] within 30 min post-injection (p.i.) and retention therein till 24 h [(2.56±0.25)% IA)/g], upto which the study was continued. The complex exhibited fast clearance from the non-target organs with favorable tumor/blood and tumor/muscle ratios [(5.09±0.18)% and (284.44±3.25)% at 24 h p.i.]. Conclusion: The complex exhibited good uptake and retention in the tumor along with encouraging target to non-target ratio. Preliminary biological studies indicated the promising attributes of the agent towards its use for targeted radiotherapy.

D-Serine is a physiological coagonist of the N-methyl D-aspartate (NMDA) type of glutamate receptor-a key excitatory neurotransmitter receptor in the brain. D-Serine appears to be a part of the synapse through a variety of transporters located on both neurons and astrocytes. The development of 99mTc radiolabeled amino acid based radiopharmaceuticals for imaging a variety of tumors has found to be useful in diagnostic imaging. Diethylene triamine penta acetic acid (DTPA) is one of the most well-known chelating reagent for the production of stable complexes with various heavy metal ions. We have synthesized [DTPA-bis(D-ser)] in 90% yield and analyzed the chelate by spectroscopic techniques. The DBDSC chelate binds to 99mTc with high efficiency at ambient temperature. The resulting chelate is stable under physiological conditions (37oC, pH=7.4) for at least 24 h after radiocomplexation. The receptor binding studies of 99mTc-[DTPA-bis(D-ser)] in established lung adeno carcinoma A549 exhibited Kd value to be 26nM. A549 Tumor in athymic mice was accumulated in the γ-images. The major accumulation of the radiotracer was observed in tumor, followed by kidneys. 99mTc-[DTPA-bis(D-ser)] has promising utility as SPECT-radiopharmaceutical.

Phenylacetate has been reported to have a potent anti-proliferative and anti-differentiating effect in haematological malignancies and in solid tumours at non-toxic concentrations. This study is a preliminary investigation of 131I-radiolabelled 4-iodophenylacetic acid as a potential radiopharmaceutical equivalent. Radiolabelling by isotope exchange gave a radiochemical yield of 53 ± 6 %, and a radiochemical purity of 97.8 ± 1.2 %, as qualified by HPLC. The labelled product was used in Sprague Dawley rats and athymic nude (balb/c) mice xenografted with WHCO1 cells (an oesophageal cancer cell line). Dynamic and static scans were carried out on rats with a SPECT camera to determine the biodistribution of 4-[131I]-iodophenylacetic acid. No target organ was found after 5 h with fast excretion from all organs via the kidney into the urine. Ex vivo studies (termination 5 h after injection) were performed in 12 xenograft mice carrying tumours of 5-8 mm on their right flank. Tumour uptake of 4 + 0.4 % ID/g was recorded with a tumour to background ratio of 2. As the blood pool still contains high levels of activity after 5 h in mice, increased tumour uptake may occur at later time points, which might warrant further investigation.