Synthesis optimization of 2-(4-N-[11C]methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB), ß-amyloid PET imaging tracer for Alzheimer's disease diagnosis.

[11C]PIB is the most used amyloid plaques-specific positron-emitting radiotracers. The radiosynthesis of this compound, carried out by methylation of its precursor with [11C]methyl triflate in 2-butanone, has been improved optimizing the initial concentration and the purification method. Two HPLC methods were compared: good radiochemical yields, specific activities, and chemical purity above 98% were achieved by using as eluant acetonitrile/citrate and formulation in 10% ethanol.

Treatment with tandem [90Y]DOTA-TATE and [177Lu]DOTA-TATE of neuroendocrine tumours refractory to conventional therapy.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues has been demonstrated to be an effective therapeutic option in patients with disseminated neuroendocrine tumours (NET). Treatment with tandem [(90)Y]DOTA-TATE and [(177)Lu]DOTA-TATE may improve the efficacy of PRRT without increasing the toxicity. In a phase II study we evaluated the feasibility of combined PPRT with a high-energy beta emitter ((90)Y) and a medium-energy beta/gamma emitter ([(177)Lu) in patients with metastatic NET refractory to conventional therapy. METHODS: A group of 26 patients with metastatic NET were treated with four therapeutic cycles of alternating [[(177)Lu]DOTA-TATE (5.55 GBq) and [(90)Y]DOTA-TATE (2.6 GBq). A dosimetric evaluation was carried out after administration of [[(177)Lu]DOTA-TATE to calculate the absorbed doses in healthy organs. The acute and long-term toxicities of repeated treatment were analysed. PRRT efficacy was evaluated according to RECIST. RESULTS: Administration of tandem [(90)Y]DOTA-TATE and [[(177)Lu]DOTA-TATE induced objective responses in 42.3 % of patients with metastatic NET with a median progression-free survival longer than 24 months. Of patients with pretreatment carcinoid syndrome, 90 % showed a symptomatic response or a reduction in tumour-associated pain. The cumulative biologically effective doses (BED) were below the toxicity limit in the majority of patients, in the absence of renal function impairment. CONCLUSION: The results of our study indicates that combined [(90)Y]DOTA-TATE and [(177)Lu]DOTA-TATE therapy is a feasible and effective therapeutic option in NET refractory to conventional therapy. Furthermore, the absence of kidney damage and the evaluated cumulative BEDs suggest that increasing the number of tandem administrations is an interesting approach.

A single-chain fragment against prostate specific membrane antigen as a tool to build theranostic reagents for prostate cancer.

Prostate carcinoma is the most common non-cutaneous cancer in developed countries and represents the second leading cause of death. Early stage androgen dependent prostate carcinoma responds well to conventional therapies, but relatively few treatment options exist for patients with hormone-refractory prostate cancer. One of the most suitable targets for antibody-mediated approaches is prostate specific membrane antigen (PSMA) which is a well known tumour associated antigen. PSMA is a type II integral cell-surface membrane protein that is not secreted, and its expression density and enzymatic activity are increased progressively in prostate cancer compared to normal prostate epithelium, thereby making PSMA an ideal target for monoclonal antibody imaging and therapy. To obtain a small protein that can better penetrate tissue, we have engineered a single-chain variable fragment (scFv) starting from the variable heavy and light domains of the murine anti-PSMA monoclonal antibody D2B. scFvD2B was analysed in vitro for activity, stability, internalisation ability and in vivo for targeting specificity. Maintenance of function and immunoreactivity as well as extremely high radiolabelling efficiency and radiochemical purity were demonstrated by in vitro assays and under different experimental conditions. Despite its monovalent binding, scFvD2B retained a good strength of binding and was able to internalise around 40% of bound antigen. In vivo we showed its ability to specifically target only PSMA expressing prostate cancer xenografts. Due to these advantageous properties, scFvD2B has the potential to become a good theranostic reagent for early detection and therapy of prostate cancers.

State of the art of palliative therapy.

Bone pain in advanced stages of cancer significantly decreases the patient's quality of life having a great impact on physical, physiological and social functioning. About 65% of patients with prostate or breast cancer will experience symptomatic skeletal metastases. Bone pain sustained by osseous metastases represents the most frequent kind of pain and its clinical presentation and characteristics differ from other type of neoplastic pain (i.e., neuropathic or visceral ones). Pathophysiology of bone pain is not yet completely understood but a general mechanism including infiltration of bone tissue associated with osteolysis and release of biological active molecules able to stimulate peripheral nervous terminals, seems to be principally involved. In oncological practice, painful skeletal metastases are managed by different multidisciplinary modalities which include the use of systemic analgesics (i.e., bisphosphonates), antineoplastic agents (i.e., hormones and chemotherapeutics), external beam radiotherapy, interventional radiology and radiopharmaceuticals. In this review we will discuss the state of the art of palliative therapy of bone pain with particular emphasis to the current approved radiopharmaceuticals, focusing on indications, patient selection, efficacy and toxicity. Some remarks on new or under developing strategies in systemic metabolic radiopharmaceutical therapy will be reported.

Imaging of neuroendocrine tumours with gamma-emitting radiopharmaceuticals.

Nuclear medicine can image some tumors by means of receptor specific radiopharmaceuticals, and offers the possibility to characterize cancer through the detection of its receptor expression. This is the case of neuroendocrine tumours (NETs), that are visualized by different radiolabelled somatostatin analogues that bind 5 distinct somatostatin receptor types (named sstr1-5) that show different tissue distribution. The subtypes sstr2 and sstr5 are the most commonly expressed in NETs. Until now the most widely used radiolabelled somatostatin analogue for planar and single photon emission computed tomography (SPECT) has been [(111)In]pentetreotide, because of its commercial availability. Other analogues labelled with gamma emitting radionuclides are [(99m)Tc]EDDA/HYNIC-TOC, [(99m)Tc]P829, [(111)In]DOTA-lanreotide, [(111)In]DOTA-NOC-ATE, [(111)In]DOTA-BOC-ATE. However, these compounds have not been successful for the routine use. Moreover, NETs express various receptors that can be depicted by different radiopharmaceuticals, such as [(123)I]VIP and [(111)In]GLP-1. Besides this, some precursors of the catecholamines metabolism, as meta-iodo-benzyl-guanidine (MIBG), labelled with (123)I or (131)I, accumulates in neuroendocrine tissues, in particular those of sympathoadrenal lineage. MIBG scintigraphy is currently indicated for neuroblastoma, paraganglioma and phaeocromocitoma. An impressive technological progress has been achieved recently with PET and, in particular, with the development of hybrid instrumentations (PET/CT) combining nuclear imaging with radiological imaging providing both functional and morphologic information. Among positron emitting tracers, the [(18)F]FDG is the most diffuse in oncology, but other more effective tracers are available for NETs, such as the analogues labelled with 68Ga. The diagnostic sensitivity and accuracy of these technology is superior to that of gamma emitting radiopharmaceuticals, but the fact that they are not still registered limits their use in the clinical practice. This overview summarizes the state of art of NETs imaging, focusing the attention mainly on gamma-emitting tracers.

Treatment with tandem [(90)Y]DOTA-TATE and [(177)Lu] DOTA-TATE of neuroendocrine tumors refractory to conventional therapy: preliminary results.

AIM: Neuroendocrine tumors over-express somatostatin receptors and literature data have demonstrated the efficacy of the peptide receptor radionuclide therapy with somatostatin analogues labelled with high activities of b-emitting radioisotopes, such as (90)Y and (177)Lu. Yttrium-90 is a pure high energy b-emitter while (177)Lu is a b/g emitter of medium energy. We decided to evaluate an original tandem treatment based on administration of radiolabeled [DOTA(0),Tyr(3)]octreotate (DOTA-TATE) alternating (177)Lu and 90Y. Aim of this study was to evaluate the feasibility, the efficacy and the toxicity of this treatment in neuroendocrine tumors expressing somatostatin receptors relapsed or refractory to conventional therapies. METHODS: Patients were treated with four therapeutic cycles alternating [(177)Lu]DOTA-TATE (5.55 GBq) and [(90)Y]DOTA-TATE (2.6 GBq). Dosimetric evaluation after administration of [(177)Lu]DOTA-TATE allows to calculate the absorbed doses in healthy organs. Blood samples were collected at 5 min, 1, 6, 24, 48, 72, 96 h and scintigraphy was performed once a day for four days after administration. Toxicity was evaluated considering hematological parameters and renal toxicity was evaluated also by the glomerular filtration rate (GFR). Efficacy related with RECIST criteria. RESULTS: Up to now 26 patients entered the study and 16 patients completed all cycles. Treatment was well tolerated with no adverse event registered. No damage to healthy organs was revealed in accordance with the calculated absorbed doses. We had a partial response in 10/15 patients evaluated three months after the fourth treatment. CONCLUSIONS: Up to now only a few patients participated in and concluded this study; preliminary results are encouraging and indicate the feasibility of the study.

Absorbed dose and biologically effective dose in patients with high-risk non-Hodgkin's lymphoma treated with high-activity myeloablative 90Y-ibritumomab tiuxetan (Zevalin).

PURPOSE: The aim of this study was to carry out two different dose estimation approaches in patients with non-Hodgkin's lymphoma (NHL) treated with a myeloablative amount of (90)Y-labelled ibritumomab tiuxetan (Zevalin(R)) in an open-label dose escalation study. METHODS: Twenty-seven patients with relapsed/refractory or de novo high-risk NHL receiving one myeloablative dose of (90)Y-ibritumomab tiuxetan followed by tandem stem cell reinfusion were evaluated for dose estimate. The injected activity was 30 MBq/kg in 12 patients and 45 MBq/kg in 15 patients. Dose estimation was performed 1 week prior to (90)Y-ibritumomab tiuxetan by injection of (111)In-ibritumomab tiuxetan (median activity: 200 MBq). The absorbed dose (D) and the biologically effective dose (BED) were calculated. RESULTS: The absorbed doses per unit activity (Gy/GBq) were [median (range)]: heart wall 4.6 (2.5-9.7), kidneys 5.1 (2.8-10.5), liver 6.1 (3.9-10.4), lungs 2.9 (1.5-6.8), red marrow 1.0 (0.5-1.7), spleen 7.0 (1.5-14.4) and testes 4.9 (2.9-16.7). The absorbed dose (Gy) for the 15 patients treated with 45 MBq/kg were: heart wall 17.0 (8.7-25.4), kidneys 17.1 (7.9-22.4), liver 20.8 (15.4-28.3), lungs 8.1 (5.4-11.4), red marrow 3.1 (2.0-4.0), spleen 26.2 (17.0-35.6) and testes 17.3 (9.0-28.4). At the highest activities the acute haematological toxicity was mild or moderate and of very short duration, and it was independent of the red marrow absorbed dose. No secondary malignancy or treatment-related myelodysplastic syndrome was observed. No non-haematological toxicity (liver, kidney, lung) was observed during a follow-up period of 24-48 months. CONCLUSION: The use of 45 MBq/kg of (90)Y-ibritumomab tiuxetan in association with stem cell autografting resulted in patients being free of toxicity in non-haematological organs. These clinical findings were in complete agreement with our dose estimations, considering both organ doses and BED values.

Serum levels of tartrate-resistant acid phosphatase-5b in breast cancer patients treated with pamidronate.

A novel immunoassay specific for the osteoclast-produced TRAP isoform 5b has been developed recently. By means of this assay we studied the usefulness of serum TRAP-5b in monitoring the response to palliative treatment with pamidronate in breast cancer patients with bone metastases. We correlated serum TRAP-5b levels with pain intensity and intake of analgesics to assess the possible utility of the marker in identifying patients who could benefit from pamidronate treatment. Twenty-eight advanced breast cancer patients with bone metastases entered the study. Patients were treated according to the following schedule: two two-week cycles of 60 mg/week pamidronate IV, with a three-week interval in between (six infusions over seven weeks), followed by one infusion every three weeks for a total of 24 infusions over a treatment period of 61 weeks. Blood samples were taken before the start of treatment and before each infusion during two treatment cycles. To measure serum TRAP levels we employed the new immunoassay kit BoneTRAP produced by Suomen Bioanalytiikka Oy (SBA), Oulu, Finland. In order to assess the usefulness of this marker in evaluating the response to pamidronate treatment we divided patients into two groups (group A, worsened; group B, improved) with respect to pain trend and analgesic intake. Our results did not show any statistically significant difference in baseline serum TRAP levels in the two groups. However, one week after the first pamidronate infusion TRAP-5b serum levels decreased by 39% and 18% in groups A and B, respectively (p=0.01); these levels persisted throughout the treatment period. In conclusion, a decrease in TRAP-5b serum levels may reflect the pharmacological activity of pamidronate and seems to predict pain relief and a reduction in analgesic consumption.