Development of a novel radiobromine-labeled sigma-1 receptor imaging probe.

INTRODUCTION: Sigma-1 receptor is a target for tumor imaging. In a previous study, we synthesized a vesamicol analog, (+)-2-[4-(4-bromophenyl)piperidino]cyclohexanol [(+)-pBrV], with a high affinity for sigma-1 receptor, and synthesized radiobrominated (+)-pBrV. This radiobrominated (+)-pBrV showed high tumor uptake in tumor-bearing mice; however, radioactivity accumulation in normal tissues, such as the liver, was high. We assumed that the accumulation of (+)-pBrV in the non-target tissues was partially derived from its high lipophilicity; therefore, we synthesized and evaluated (+)-4-[1-(2-hydroxycyclohexyl)piperidine-4-yl]-2-bromophenol [(+)-BrV-OH], which is a more hydrophilic compound. Although we aimed to develop a PET tracer using 76Br, in these initial studies, we used 77Br because of its longer half-life. METHODS: (+)-[77Br]BrV-OH was synthesized using the chloramine-T method with a radiochemical purity of 95%. Lipophilicity and affinity for sigma-1 receptor of (+)-[77Br]BrV-OH were determined, and biodistribution experiments were performed. We also performed an in vivo blocking study by co-injecting excess amounts of the sigma-1 receptor ligand, SA4503, into mice. RESULTS: The lipophilicity and affinity for sigma-1 receptor of (+)-[77Br]BrV-OH were lower than those of (+)-[77Br]pBrV. (+)-[77Br]BrV-OH also showed high tumor uptake in biodistribution experiments in DU-145 tumor-bearing mice,. Although (+)-[77Br]pBrV was retained in most tissues, (+)-[77Br]BrV-OH was cleared from these tissues. In blocking studies, the co-injection of SA4503 significantly decreased the tumor uptake of (+)-[77Br]BrV-OH. CONCLUSION: These results indicate that (+)-[76Br]BrV-OH has potential as a PET probe for sigma-1 receptor imaging.

Preparation and evaluation of an astatine-211-labeled sigma receptor ligand for alpha radionuclide therapy.

INTRODUCTION: Sigma receptors are overexpressed in a variety of human tumors, making them potential targets for radionuclide receptor therapy. We have previously synthesized and evaluated (131)I-labeled (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol [(+)-[(131)I]pIV], which has a high affinity for sigma receptors. Therefore, (+)-[(131)I]pIV significantly inhibited tumor cell proliferation in tumor-bearing mice. In the present study, we report the synthesis and the in vitro and in vivo characterization of (+)-[(211)At]pAtV, an (211)At-labeled sigma receptor ligand, that has potential use in alpha-radionuclide receptor therapy. METHODS: The radiolabeled sigma receptor ligand (+)-[(211)At]pAtV was prepared using a standard halogenation reaction generating a 91% radiochemical yield with 98% purity after HPLC purification. The partition coefficient of (+)-[(211)At]pAtV was measured. Cellular uptake experiments and in vivo biodistribution experiments were performed using a mixed solution of (+)-[(211)At]pAtV and (+)-[(125)I]pIV; the human prostate cancer cell line DU-145, which expresses high levels of the sigma receptors, and DU-145 tumor-bearing mice. RESULTS: The lipophilicity of (+)-[(211)At]pAtV was similar to that of (+)-[(125)I]pIV. DU-145 cellular uptake and the biodistribution patterns in DU-145 tumor-bearing mice at 1h post-injection were also similar between (+)-[(211)At]pAtV and (+)-[(125)I]pIV. Namely, (+)-[(211)At]pAtV demonstrated high uptake and retention in tumor via binding to sigma receptors. CONCLUSION: These results indicate that (+)-[(211)At]pAtV could function as an new agent for alpha-radionuclide receptor therapy.

Reversible posterior leukoencephalopathy syndrome accompanying eclampsia: correct diagnosis using preoperative MRI.

Reversible posterior leukoencephalopathy syndrome (RPLS) is characterized by clinical symptoms such as seizures, visual disturbance, and altered mental status. It also presents abnormal findings on computed tomography (CT) and magnetic resonance imaging (MRI) indicating cerebral edema in the white matter of the occipital, temporal, and parietal lobes. Both the clinical symptoms and abnormal imaging findings can be reversed by controlling blood pressure or treating the underlying condition including infection. This report describes a patient with RPLS that occurred secondary to eclampsia. A 26-year-old female, gravida 0 para 0, developed weakness and pain in her upper and lower extremities and gait disturbance during the 34th week of pregnancy, and severe pregnancy-induced hypertension near the end of the 37th week. On the first day of the 38th week, she developed constricted visual fields and complained of visual illusions. MRI revealed a high-signal-intensity area in the right occipital lobe. Immediately after MRI, the patient had a 10-sec tonic convulsion. Diagnosed with eclampsia, she underwent emergency cesarean section. MRI on the 2nd postoperative day showed that the high-signal-intensity area was slightly improved. Her visual illusions were diminished by the 4th postoperative day, and almost all subjective symptoms disappeared by the 7th postoperative day. The patient was discharged at 12th postoperative day. We recommend MRI not only for symptomatic patients with suspected RPLS, but also for asymptomatic patients with severe pregnancy-induced hypertension. If findings such as cerebral edema are observed on MRI, immediate delivery should be considered before eclamptic seizures or exacerbation of neurological symptoms.

Feasibility study of oral cyclophosphamide salvage therapy for the treatment of heavily pretreated patients with recurrent epithelial ovarian cancer.

BACKGROUND: In patients with relapsed ovarian cancer, the objectives of salvage therapy are considered to be maintenance of quality of life and prolongation of patient survival. Chemotherapy using oral agents could be a good choice for salvage therapy. We reassessed the usefulness of oral cyclophosphamide (CPA) salvage therapy for heavily pretreated patients with recurrent epithelial ovarian cancer. METHODS: We evaluated the effects and toxicities of 100 mg oral dose (50 mg twice a day) of CPA for 14 patients who had undergone an average of 3 chemotherapy treatments before enrolling in our study. RESULTS: One patient showed partial response and 8 developed stable diseases. Median time to progression was 3 months (range 1-13 months) and median survival was 7 months (range 2-28 months). Common Terminology Criteria for Adverse Events (CTCAE) grade 3/4 adverse effects were leukopenia (7.1%), neutropenia (14.3%), thrombocytopenia (7.1%), and nausea/vomiting (21.4%). CONCLUSION: Although moderate gastrointestinal toxicity was observed, oral CPA therapy contributed to improving the survival of heavily pretreated patients with recurrent epithelial ovarian cancer. A well-designed phase II trial in this regard is awaited.