Current Radiopharmaceuticals - Volume 3, Issue 1, 2010

Objectives: The aim of this research was to synthesize radiolabeled peptidomimetic integrin αvβ3 antagonist with 99mTc for rapid targeting of integrin αvβ3 receptors in tumor to produce a high tumor to background ratio. Methods: The amino terminus of 4-[2-(3,4,5,6-tetra-hydropyrimidin-2-ylamino)-ethyloxy]benzoyl-2-(S)-[N-(3-amino-- neopenta-1-carbamyl)]-aminoethylsulfonyl- amino-β-alanine hydrochloride (IAC) was conjugated with N-hydroxysuccinimide ester of HYNIC and labeled with 99mTc using tricine with either 1,5-pyridinedicarboxylic acid (PDA) or ethylenediamine-N,N'-diacetic acid (EDDA) as the co-ligand. The products, 99mTc EDDA2/HYNIC-IAC (P1) and 99mTc PDA (tricin)/HYNIC-IAC (P2) were subjected to in vitro serum stability, receptor-binding, biodistribution and imaging studies. Results: P1 and P2 were synthesized with an overall yield of >80%. P1 was slightly more stable than P2 when incubated in serum at 37 °C for 18 hrs (84 vs 77% intact). The In vitro receptor-binding of P1 was higher than that of P2 (78.02 ± 13.48 vs 51.05 ± 14.05%) when incubated with αvβ3 at a molar excess (0.8 μM). This receptor binding was completely blocked by a molar excess of an unlabeled peptidomimetic antagonist. Their differences shown in serum stability and the receptor-binding appeared to be related to their biological behaviors in tumor uptake and retention; the 1 h tumor uptakes of P1 and P2 were 3.17±0.52 and 2.13±0.17 % ID/g, respectively. P1 was retained in the tumor longer than P2. P1 was excreted primarily through the renal system whereas P2 complex was excreted equally via both renal and hepatobiliary systems. Thus, P1 was retained in the whole-body with 27.25 ± 3.67% ID at 4 h whereas 54.04 ± 3.57% ID of P2 remained in the whole-body at 4 h. This higher whole-body retention of P2 appeared to be resulted from a higher amount of radioactivity retained in liver and intestine. These findings were supported by imaging studies showing higher tumor-to-abdominal contrast for P1 than for P2 at 3 h postinjection. Conclusions: P1 showed good tumor targeting properties with a rapid tumor uptake, prolonged tumor retention and fast whole-body clearance kinetics. These findings warrant further investigation of the HYNIC method of 99mTc labeling of other peptidomimetic antagonists using EDDA as a coligand.

In vitro and ex vivo measurements have shown that the binding of the selective high-affinity agonist, S14506 (1-[2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxy-naphthyl)piperazine), to 5-HT1A receptors, is similar in affinity (Kd = 0.79 nM) and extent (Bmax) to that of the antagonist, WAY 100635. We aimed to test whether S14506, labeled with a positron- emitter, might serve as a radioligand for imaging brain 5-HT1A receptors in vivo with positron emission tomography (PET). Here we evaluated [11C]S14506 and [18F]S14506 in rat and rhesus monkey in vivo. After intravenous administration of [11C]S14506 into rat, radioactivity entered brain, reaching 210% SUV at 2 min. Radioactivity uptake into brain was higher (∼ 350% SUV) in rats pre-treated with the P-glycoprotein (P-gp) inhibitor, cyclosporin A. In rhesus monkey, peak brain uptake of radioactivity after administration of [11C]S14506 or [18F]S14506 was also moderate and for [11C]S14506 increased from ∼ 170% SUV after 7 min, to 240% SUV in a monkey pre-treated with the P-gp inhibitor, tariquidar. The ratios of radioactivity in 5-HT1A receptor-rich regions, such as cingulate or hippocampus to that in receptor- poor cerebellum reached between 1.35 and 1.5 at 60 min for both [11C]S14506 and [18F]S14506. [11C]S14506 gave one major polar radiometabolite in monkey plasma, and [18F]S14506 gave three and two more polar radiometabolites in rat and monkey plasma, respectively. The rat radiometabolites of [18F]S14506 did not accumulate in brain. [18F]S14506 was not radiodefluorinated in monkey. Thus, despite high-affinity and lack of troublesome brain radiometabolites, both [11C]S14506 and [18F]S14506 were ineffective for imaging rat or monkey brain 5-HT1A receptors in vivo, even under P-gp inhibited conditions. Explanations for the failure of these radioligands are offered.

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: The group ER was treated with EMP 0.2 mg/d and external irradiation 3 x 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.

Pheochromocytoma is a rare neuroendocrine tumour. The prognosis after metastasis is poor, but there have been rare cases of prolonged survival of up to 26 years. Treatments for malignant phaeochromocytoma include surgical debulking, pharmacological control of hormone-mediated symptoms, 131I-metaiodobenzylguanidine (MIBG) therapy, chemotherapy and hormone therapy such as somatostatin analogues. We report the case of a patient, treated only with 131IMIBG therapy, who has survived 28 years since her diagnosis in 1981. The primary lesion was removed in 1982 by adrenectomy. In 1987, urinary catecholamines began to rise, heralding the onset of multiple bone and lung metastases. Her only treatment has been six doses of 131I-MIBG therapy between 1988 and 2003, (total of 22,804MBq). These treatments have relieved pain and led to the resolution of some of the metastatic lesions. She is now 81 years old and is currently very well and asymptomatic, despite evidence of residual thoracic and lumbar vertebral metastases.

Medulloblastoma, the most common pediatric brain tumor, is difficult to treat because conventional therapeutic approaches result in significant toxicity to normal central nervous system tissues, compromising quality of life. Given the fact that medulloblastomas express the somatostatin subtype 2 receptor, [177Lu-DOTA0,Tyr3]octreotate ([177Lu]DOTA-TATE) could be a potentially useful targeted radiotherapeutic for the treatment of this malignancy. The current study was undertaken to evaluate this possibility in preclinical models of D341 MED human medulloblastoma by comparing the properties of [177Lu]DOTA-TATE to those of glucose-[125I-Tyr3]-octreotate ([125I]Gluc-TOCA), a radiopeptide previously shown to target this cell line. In vitro assays indicated that both labeled peptides exhibited similar cell-associated and internalized radioactivity after a 30-min incubation at 37° C; however, at the end of the 4 h incubation period, the internalized radioactivity for [177Lu]DOTA-TATE (6.22 ± 0.75%) was nearly twice that for [125I]Gluc-TOCA (3.16 ± 0.27%), with similar differences seen in total cell-associated radioactivity levels. Consistent with the results from the internalization assays, results from paired-label tissue distribution studies in athymic mice with subcutaneous D341 MED medulloblastoma xenografts showed a similar degree of tumor accumulation for [177Lu]DOTA-TATE and [125I]Gluc-TOCA at early time points but by 24 h, a more than 5-fold advantage was observed for the 177Lu-labeled peptide. Tumor-to-normal tissue ratios generally were more favorable for [177Lu]DOTA-TATE at all time points, due in part to its lower accumulation in normal tissues except kidneys. Taken together, these results suggest that [177Lu]DOTA-TATE warrants further investigation as a targeted radiotherapeutic for medulloblastoma treatment.

Molecular imaging via Single Photon Emission Computed Tomography (SPECT) holds considerable promise for analysis of metabolism and bio-distribution of drugs in addition to imaging of diseased states. While the related Positron Emission Tomography (PET) imaging offers higher resolution images, SPECT is considered the more practical approach to nuclear imaging for routine diagnostic use. One of the attractive features of SPECT is its utilization of medium to long-lived radioisotopes, particularly radio-iodinated species. This mini-review will survey recent advances in radioiodination, including synthetic chemistry and post-labeling purification methods.

Colorectal cancer presents with metastatic disease in approximately 20% of newly diagnosed patients [1]. As surgery offers hope for a cure and only 25% of cases are resectable, regional therapy is an important option for the remaining patients. Selective Internal Radiation Therapy (SIRT) is a therapy that has been shown to provide significant local control in the liver and is generally well tolerated. Despite appropriate steps to limit the overall radiation to liver tumors, escaped particles may cause significant damage to local organs. In the case presented, SIRT was performed along with embolization of select stomach vasculature. A post-procedure radiation detection scan was negative. Unfortunately, the patient later developed radiation induced gastric ulceration where microscopic beads were demonstrated on gastric biopsy.

Technegas, a carbon-coated Tc-99m nanoparticulate aerosol invented by Burch at the Australian National University in 1984, was introduced to the medical community in 1986 with two reports of its use as a new ventilation agent for lung imaging. Since that time, more than 1,500 Technegas machines have been distributed in hospitals and clinics in 54 countries, and more than 2 million Technegas ventilation studies have been completed. This review provides a synopsis of the more than 250 publications, abstracts and reports on Technegas. Technegas compares favourably with other commonly used ventilation (V) imaging agents including Xenon-133 and Krypton-81m gases, and several technetium-99m aerosol formulations. It is an effective agent for pulmonary ventilation (V) studies, particularly for detecting pulmonary embolisms when used in combination with perfusion (Q) scintigraphy by a technique known as ventilation/local perfusion image-mismatch (V/Q) imaging. Other applications for Technegas include non-clinical V/Q imaging in large animals, gastric emptying studies with Technegas-labeled meals, powder formulation studies of Technegas-labeled drugs, thrombosis detection using a precipitated formulation of Technegas (Thrombotrace) and pulmonary clearance studies using a derivative form called Pertechnegas.

Biodistribution of the monoclonal antibody (mAb 9d9f9) against the vascular endothelial growth factor receptor- 3 (VEGFR-3) is studied here in the rat. VEGFR-3 is expressed on endothelial cells of lymphatic endothelium during the tissue growth. The mAb9d9f9 is the first specific molecular marker to the endothelial cells of high venules. The specificity was detected with immunohistochemistry of tissue samples. Materials The affinity of 125I-mAb 9d9f9 was determined in HEL leukemia cells expressing the extracellular receptor and the biodistribution was detected both by external imaging and tissue sampling in the tumor model. The imaging result with subcutaneous injections was compared to the imaging after intravenous injections. Results Targeting to the induced mammary tumors in rat was detected with immunoscintigraphy of 125I-mAb. The imaging after subcutaneous administration showed lower uptake in liver, spleen, heart and stomach than the imaging after intravenous administration. The mAb 9d9f9 accumulated to the parasternal lymphatic vessels at 16 days after the subcutaneous injections. Conclusion The mAb 9d9f9 visualized the routes of lymphatic circulation probably based on binding to this transmembrane lymphatic endothelial receptor. Immunodetection of the tumors in rat was, however, possible with these antibodies targeting to the endothelial cells lining the vascular system.