Targeted Radionuclide Therapy: A Historical and Personal Review.

This review traces the development of targeted radionuclide therapy (TRT) (the Magic Bullet) from the discovery of radioactivity in nature and the subsequent discovery of artificial radioactivity (the production of radioactive isotopes of stable elements) to the current status of TRT in the medical literature and clinical practice. With the availability of radioisotopes of iodine, initially to study thyroidal iodine kinetics, it was soon observed that sufficient amounts of radiation could control thyroid hyperfunction. Shortly thereafter, when radioiodine was administered to a patient with differentiated thyroid carcinoma whose hypermetabolism was secondary to excess thyroid hormone production, it was observed that radioiodine also had an antitumor effect. The concept of the Magic Bullet has since been extended to other disease states such as (1) 131I-meta-iodobenzylguanidine (131I-MIBG) to treat malignant and metastatic pheochromocytomas and paragangliomas; (2) 131I-tositumomab, a radioiodinated anti-CD20 IgG to treat CD20 expressing non-Hodgkins lymphoma. In recent years, other ß-emitting radionuclides, Yttrium-90 (90Y) and Lutetium-177 (177Lu), have been added to this list. These radiometals have different physical properties that were thought to be possibly more effective than radioiodine. 90Y was initially used to radio-label somatostatin analogues to treat metastatic neuroendocrine tumors but has virtually been replaced by 177Lu since the physical characteristics of the latter appear to be better suited to effectively irradiate the micrometastases of neuroendocrine tumors. A similar evolution is taking place in the development of a targeted radionuclide therapeutic that recognizes prostate-specific membrane antigen (PSMA), an epitope expressed in increased amounts in prostate carcinoma. Both an anti-PSMA immunoglobulin (J591) and a small molecule glutamase ligand are currently being evaluated as targeted radionuclide therapy agents. Radionuclides that have affinity for the calcium hydroxyapatite in bone have been used to relieve bone pain due to tumor metastases based on increased deposition of the bone seeking radiometals at the osteoblastic interface of the tumor metastases and boney matrix. Most of these trials have been in patients with metastatic prostate cancer since there are few other options. In this regard, targeted radionuclide therapy has come full circles as the most recent addition to this anti-tumor arsenal is a radioisotope of Radium, 223Ra, an alpha emitter which has a greater radiobiologic effect but limited range in tissue thus adding an element of safety when treating marrow metastases. Other alpha emitting radiometals are currently being evaluated as alternative radiometals in place of 90Y and 177Lu to label targeting molecules.

Phase 1/2 study of fractionated dose lutetium-177-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 (177 Lu-J591) for metastatic castration-resistant prostate cancer.

BACKGROUND: Prostate cancer is radiosensitive. Prostate-specific membrane antigen (PSMA) is selectively overexpressed on advanced, castration-resistant tumors. Lutetium-177-labeled anti-PSMA monoclonal antibody J591 (177 Lu-J591) targets prostate cancer with efficacy and dose-response/toxicity data when delivered as a single dose. Dose fractionation may allow higher doses to be administered safely. METHOD: Men with metastatic castration-resistant prostate cancer refractory to or refusing standard treatment options with normal neutrophil and platelet counts were enrolled in initial phase 1b dose-escalation cohorts followed by phase 2a cohorts treated at recommended phase 2 doses (RP2Ds) comprising 2 fractionated doses of 177 Lu-J591 2 weeks apart. 177 Lu-J591 imaging was performed after treatment, but no selection for PSMA expression was performed before enrollment. Phase 2 patients had circulating tumor cell (CTC) counts assessed before and after treatment. RESULTS: Forty-nine men received fractionated doses of 177 Lu-J591 ranging from 20 to 45 mCi/m2 ×2 two weeks apart. The dose-limiting toxicity in phase 1 was neutropenia. The RP2Ds were 40 mCi/m2 and 45 mCi/m2 ×2. At the highest RP2D (45 mCi/m2 ×2), 35.3% of patients had reversible grade 4 neutropenia, and 58.8% of patients had thrombocytopenia. This dose showed a greater decrease in prostate-specific antigen (PSA) levels and longer survival (87.5% with any PSA decrease, 58.8% with >30% decrease, 29.4% with >50% decrease; median survival, 42.3 months [95% confidence interval, 19.9-64.7]). Fourteen of 17 (82%) patients with detectable CTCs experienced a decrease in CTC count. Overall, 79.6% of patients had positive PSMA imaging; those with less intense PSMA imaging tended to have poorer responses. CONCLUSION: Fractionated administration of 177 Lu-J591 allowed higher cumulative radiation dosing. The frequency and depth of PSA decrease, overall survival, and toxicity (dose-limiting myelosuppression) increased with higher doses.

Phase 1 Study of High-Specific-Activity I-131 MIBG for Metastatic and/or Recurrent Pheochromocytoma or Paraganglioma.

Context: No therapies are approved for the treatment of metastatic and/or recurrent pheochromocytoma or paraganglioma (PPGL) in the United States. Objective: To determine the maximum tolerated dose (MTD) of high-specific-activity I-131 meta-iodobenzylguanidine (MIBG) for the treatment of metastatic and/or recurrent PPGL. Design: Phase 1, dose-escalating study to determine the MTD via a standard 3 + 3 design, escalating by 37 MBq/kg starting at 222 MBq/kg. Setting: Three centers. Patients: Twenty-one patients were eligible, received study drug, and were evaluable for MTD, response, and toxicity. Intervention: Open-label use of high-specific-activity I-131 MIBG therapy. Main Outcome Measures: Dose-limiting toxicities, adverse events, radiation absorbed dose estimates, radiographic tumor response, biochemical response, and survival. Results: The MTD was determined to be 296 MBq/kg on the basis of two observed dose-limiting toxicities at the next dose level. The highest mean radiation absorbed dose estimates were in the thyroid and lower large intestinal wall (each 1.2 mGy/MBq). Response was evaluated by total administered activity: four patients (19%), all of whom received >18.5 GBq of study drug, had radiographic tumor responses of partial response by Response Evaluation Criteria in Solid Tumors. Best biochemical responses (complete or partial response) for serum chromogranin A and total metanephrines were observed in 80% and 64% of patients, respectively. Overall survival was 85.7% at 1 year and 61.9% at 2 years after treatment. The majority (84%) of adverse events were considered mild or moderate in severity. Conclusions: These findings support further development of high-specific-activity I-131 MIBG for the treatment of metastatic and/or recurrent PPGL at an MTD of 296 MBq/kg.

Radioactive Iodine Therapy of Differentiated Thyroid Carcinoma: Redesigning the Paradigm.

Radioactive iodine therapy has evolved over the past 70 years from treatment of known metastatic thyroid carcinoma to include adjuvant use to decrease the incidence of recurrent disease and to ablation of normal remnant tissue following thyroidectomy, even for minimal tumor involvement. Advances in laboratory testing, development of drugs useful in radioiodine treatment, as well as advances in radiation detection and imaging instrumentation, have progressively improved the utility of radioiodine therapy of differentiated thyroid carcinoma. Guidelines have proliferated and they have become more detailed and complex. This trend is likely to continue as the science and technology involved increases in sophistication and efficacy.

Radioimmunotherapy of Metastatic Prostate Cancer with ¹77Lu-DOTAhuJ591 Anti Prostate Specific Membrane Antigen Specific Monoclonal Antibody.

Prostate specific membrane antigen (PSMA) is the single most well-validated prostate cancer (PCa)-specific cell membrane antigen known. It is present in high levels in 95% of PCa, and is an ideal target to develop radiopharmaceuticals for imaging studies and radionuclide therapy. Humanized J591 monoclonal antibody (mAb) binds specifically with nanomolar affinity to the extracellular domain of PSMA. After binding, the PSMA-antibody complex is rapidly internalized, increasing the potential utility of PSMA as a target for the delivery of mAb-conjugated radionuclides or cytotoxins. J591 mAb was labeled with 177Lu at a high specific activity (10-30 mCi/mg) using DOTA as the bifunctional chelate. The preclinical data in PSMA positive xenografts, strongly suggested that 177;Lu-J591 mAb is an ideal radiopharmaceutical for RIT of metastatic PCa. Since October 2000, five clinical studies (phase I and II) were performed in subjects with metastatic castration-resistant prostate cancer (CRPC) using 177Lu-J591. The methodology and the results of these clinical studies are briefly reviewed in this article. The maximum tolerated dose (MTD) as a single dose was 70 mCi2. Based on dose fractionation (DF), MTD was 90 mCi/m2(2 doses of 45 mCi/m2, 2 wks apart). Phase II study in patients with progressive metastatic CRPC, at a dose of 65- 70 mCi/m2 resulted in significant PSA declines in 60% of the patients. While myelosuppression was the dose limiting toxicity, DF alone or in combination with docetaxel also resulted in significant PSA declines with much less toxicity. 177Lu imaging studies demonstrated accurate targeting of known metastatic sites in >90% of patients and those with stronger PSMA expression by semi-quantitative imaging had more PSA declines. These clinical studies clearly documented the potential therapeutic value of radioimmunotherapy (RIT) in metastatic PCa.

(90)Y-clivatuzumab tetraxetan with or without low-dose gemcitabine: A phase Ib study in patients with metastatic pancreatic cancer after two or more prior therapies.

BACKGROUND: For patients with metastatic pancreatic adenocarcinoma, there are no approved or established treatments beyond the 2nd line. A Phase Ib study of fractionated radioimmunotherapy was undertaken in this setting, administering (90)Y-clivatuzumab tetraxetan (yttrium-90-radiolabelled humanised antibody targeting pancreatic adenocarcinoma mucin) with or without low radiosensitising doses of gemcitabine. METHODS: Fifty-eight patients with three (2-7) median prior treatments were treated on Arm A (N=29, (90)Y-clivatuzumab tetraxetan, weekly 6.5 mCi/m(2)doses×3, plus gemcitabine, weekly 200 mg/m(2) doses×4 starting 1 week earlier) or Arm B (N=29, (90)Y-clivatuzumab tetraxetan alone, weekly 6.5 mCi/m(2)doses×3), repeating cycles after 4-week delays. Safety was the primary endpoint; efficacy was also evaluated. RESULTS: Cytopaenias (predominantly transient thrombocytopenia) were the only significant toxicities. Fifty-three patients (27 Arm A, 26 Arm B, 91% overall) completed ⩾1 full treatment cycles, with 23 (12 Arm A, 11 Arm B; 40%) receiving multiple cycles, including seven (6 Arm A, 1 Arm B; 12%) given 3-9 cycles. Two patients in Arm A had partial responses by RECIST criteria. Kaplan-Meier overall survival (OS) appeared improved in Arm A versus B (hazard ratio [HR] 0.55, 95% CI: 0.29-0.86; P=0.017, log-rank) and the median OS for Arm A versus Arm B increased to 7.9 versus 3.4 months with multiple cycles (HR 0.32, P=0.004), including three patients in Arm A surviving >1 year. CONCLUSIONS: Clinical studies of (90)Y-clivatuzumab tetraxetan combined with low-dose gemcitabine appear feasible in metastatic pancreatic cancer patients beyond 2nd line and a Phase III trial of this combination is now underway in this setting.

Use of radiopharmaceuticals in diagnostic nuclear medicine in the United States: 1960-2010.

To reconstruct reliable nuclear medicine-related occupational radiation doses or doses received as patients from radiopharmaceuticals over the last five decades, the authors assessed which radiopharmaceuticals were used in different time periods, their relative frequency of use, and typical values of the administered activity. This paper presents data on the changing patterns of clinical use of radiopharmaceuticals and documents the range of activity administered to adult patients undergoing diagnostic nuclear medicine procedures in the U.S. between 1960 and 2010. Data are presented for 15 diagnostic imaging procedures that include thyroid scan and thyroid uptake; brain scan; brain blood flow; lung perfusion and ventilation; bone, liver, hepatobiliary, bone marrow, pancreas, and kidney scans; cardiac imaging procedures; tumor localization studies; localization of gastrointestinal bleeding; and non-imaging studies of blood volume and iron metabolism. Data on the relative use of radiopharmaceuticals were collected using key informant interviews and comprehensive literature reviews of typical administered activities of these diagnostic nuclear medicine studies. Responses of key informants on relative use of radiopharmaceuticals are in agreement with published literature. Results of this study will be used for retrospective reconstruction of occupational and personal medical radiation doses from diagnostic radiopharmaceuticals to members of the U.S. radiologic technologists' cohort and in reconstructing radiation doses from occupational or patient radiation exposures to other U.S. workers or patient populations.

Phase I study of the anti-CD74 monoclonal antibody milatuzumab (hLL1) in patients with previously treated B-cell lymphomas.

Milatuzumab (hLL1), a humanized anti-CD74 monoclonal antibody, has activity in preclinical non-Hodgkin lymphoma (NHL) models. We conducted a phase 1 trial in previously treated B-cell malignancies. Dose escalation included four planned dose levels (1.5, 4, 6 and 8 mg/kg) with milatuzumab given twice weekly for 6 weeks. After dose level 1, the schedule was changed to daily (Monday-Friday) for 10 days. Twenty-two patients were treated. The most common possibly related toxicities were infusion reaction, anemia, lymphopenia, neutropenia and thrombocytopenia. Three patients experienced dose-limiting toxicity (neutropenia, neutropenia, rash) at dose levels 1, 2 and 4, respectively. Eight patients had stable disease, with no objective responses. The serum half-life of milatuzumab was ∼2 h. In seven patients, In-111 imaging showed no clear evidence of tumor targeting. The short half-life may reflect CD74 rapid internalization and presence on extratumoral tissues; this antigen sink must be overcome to capitalize on the promising preclinical activity of the drug.

Multiple myeloma: 18F-FDG-PET/CT and diagnostic imaging.

Multiple myeloma (MM) is a relatively rare hematologic disorder characterized by proliferation of plasma cells, primarily involving the bone marrow. Extramedullary involvement also occurs with poor prognosis. Asymptomatic plasma cell disorders, monoclonal gammopathy of uncertain significance, and smoldering MM, which do not require therapy, should be distinguished from symptomatic MM, which requires treatment. MM may present with CRAB, elevated Calcium levels, Renal insufficiency, Anemia, and Bone lesions (including lytic lesions and osteopenia), as well as elevated levels of serum M protein or urine M protein or both. Nonsecretory myeloma in which serum and urine M proteins are absent occurs rarely, accounting for 1%-5% of patients with myeloma, but low levels of abnormal immunoglobulins are often present. Staging of patients with MM is done according to the Durie and Salmon criteria based on laboratory testing (determination of hemoglobin, serum calcium, and serum and urine M proteins) and conventional radiography. A variety of diagnostic imaging procedures have been employed to assess the extent of disease in MM and to evaluate the response to treatment as well as provide surveillance for the detection of recurrent disease. These include whole-body x-ray, which despite its limitations is regularly used to detect lytic bone lesions; CT radiography; MRI; and a variety of radionuclide imaging procedures, with (18)F-FDG-PET/CT emerging as the radionuclide procedure of choice. Recently, the Durie-Salmon criteria have been upgrade to the Durie-Salmon PLUS system, which includes (18)F-FDG-PET/CT and MRI of the spine and pelvis.

99mTc-labeled small-molecule inhibitors of prostate-specific membrane antigen: pharmacokinetics and biodistribution studies in healthy subjects and patients with metastatic prostate cancer.

UNLABELLED: Prostate-specific membrane antigen (PSMA) is a well-established target for developing radiopharmaceuticals for imaging and therapy of prostate cancer (PCa). We have recently reported that novel (99m)Tc-labeled small-molecule PSMA inhibitors bind with high affinity to PSMA-positive tumor cells in vitro and localize in PCa xenografts. This study reports the first, to our knowledge, human data in men with metastatic PCa and in healthy male subjects. METHODS: Under an exploratory investigational new drug, using a cross-over design, we compared the pharmacokinetics, biodistribution, and tumor uptake of (99m)Tc-MIP-1404 and (99m)Tc-MIP-1405 in 6 healthy men and 6 men with radiographic evidence of metastatic PCa. Whole-body images were obtained at 10 min and 1, 2, 4, and 24 h. SPECT was performed between 3 and 4 h after injection. RESULTS: Both agents cleared the blood rapidly, with MIP-1404 demonstrating significantly lower urinary activity (7%) than MIP-1405 (26%). Both agents showed persistent uptake in the salivary, lacrimal, and parotid glands. Uptake in the liver and kidney was acceptable for imaging at 1-2 h. In men with PCa, both agents rapidly localized in bone and lymph node lesions as early as 1 h. SPECT demonstrated excellent lesion contrast. Good correlation was seen with bone scanning; however, more lesions were demonstrated with (99m)Tc-MIP-1404 and (99m)Tc-MIP-1405. The high-contrast images exhibited tumor-to-background ratios from 3:1 to 9:1 at 4 and 20 h. CONCLUSION: Compared with the standard-of-care bone scanning, (99m)Tc-MIP-1404 and (99m)Tc-MIP-1405 identified most bone metastatic lesions and rapidly detected soft-tissue PCa lesions including subcentimeter lymph nodes. Because (99m)Tc-MIP-1404 has minimal activity in the bladder, further work is planned to correlate imaging findings with histopathology in patients with high-risk metastatic PCa.

Nuclear medicine practices in the 1950s through the mid-1970s and occupational radiation doses to technologists from diagnostic radioisotope procedures.

Data on occupational radiation exposure from nuclear medicine procedures for the time period of the 1950s through the 1970s is important for retrospective health risk studies of medical personnel who conducted those activities. However, limited information is available on occupational exposure received by physicians and technologists who performed nuclear medicine procedures during those years. To better understand and characterize historical radiation exposures to technologists, the authors collected information on nuclear medicine practices in the 1950s, 1960s, and 1970s. To collect historical data needed to reconstruct doses to technologists, a focus group interview was held with experts who began using radioisotopes in medicine in the 1950s and the 1960s. Typical protocols and descriptions of clinical practices of diagnostic radioisotope procedures were defined by the focus group and were used to estimate occupational doses received by personnel, per nuclear medicine procedure, conducted in the 1950s to 1960s using radiopharmaceuticals available at that time. The radionuclide activities in the organs of the reference patient were calculated using the biokinetic models described in ICRP Publication 53. Air kerma rates as a function of distance from a reference patient were calculated by Monte Carlo radiation transport calculations using a hybrid computational phantom. Estimates of occupational doses to nuclear medicine technologists per procedure were found to vary from less than 0.01 µSv (thyroid scan with 1.85 MBq of administered I-iodide) to 0.4 µSv (brain scan with 26 MBq of Hg-chlormerodin). Occupational doses for the same diagnostic procedures starting in the mid-1960s but using Tc were also estimated. The doses estimated in this study show that the introduction of Tc resulted in an increase in occupational doses per procedure.

Extra-articular knee lesion with high fluorodeoxyglucose-uptake on positron emission tomography.

Pigmented villonodular synovitis (PVNS) is an uncommon musculoskeletal tumor that is typically benign and often diagnosed radiologically by magnetic resonance imaging (MRI). Fluorodeoxyglucose (FDG)-uptake positron emission tomography (PET) is an imaging tool primarily used in oncology to evaluate malignancy. FDG measures metabolic activity with standardized uptake value (SUV). A high SUV is suggestive of malignancy. We report a case of PVNS detected incidentally by FDG-PET as an extracapsular mass adherent to vastus medialis tendon with a high SUV of 15.1. Given the patient's history of cancer and the high SUV, the lesion was initially considered a malignancy. The objective of this case report is to illustrate that even a high-SUV mass detected with PET imaging does not necessarily indicate malignancy, and thus a benign lesion can also demonstrate such elevated signal.

Evaluation of WHO criteria for diagnosis of polycythemia vera: a prospective analysis.

We prospectively evaluated the accuracy of the 2007 World Health Organization (WHO) criteria for diagnosing polycythemia vera (PV), especially in "early-stage" patients. A total of 28 of 30 patients were diagnosed as PV owing to an elevated Cr-51 red cell mass (RCM), JAK2 positivity, and at least 1 minor criterion. A total of 18 PV patients did not meet the WHO criterion for an increased hemoglobin value and 8 did not meet the WHO criterion for an increased hematocrit value. Bone marrow morphology was very valuable for diagnosis. Low serum erythropoietin (EPO) values were specific for PV, but normal EPO values were found at presentation (20%). We recommend revision of the WHO criteria, especially to distinguish early-stage PV from essential thrombocythemia. Major criteria remain JAK2 positivity and increased red cell volume, but Cr-51 RCM is mandatory for patients who do not meet the defined elevated hemoglobin or hematocrit value (>18.5 g/dL and 60% in men and >16.5 g/dL and 56% in women, respectively). Minor criteria remain bone marrow histology or a low serum EPO value. For patients with a normal EPO value, marrow examination is mandatory for diagnostic confirmation. Because the therapies for myeloproliferative disorders differ, our data have major clinical implications.

Bone marrow recovery and subsequent chemotherapy following radiolabeled anti-prostate-specific membrane antigen monoclonal antibody j591 in men with metastatic castration-resistant prostate cancer.

Radioimmunotherapy (RIT) has demonstrated efficacy with acceptable toxicity leading to approval in non-Hodgkin's lymphoma, but has been slower to develop for the treatment of advanced solid tumors. Prostate cancer (PC) represents a good candidate for RIT based upon high exposure to circulating antibodies at common disease sites with a specific, highly expressed cell-surface antigen of prostate-specific membrane antigen. Four phase I and II trials utilizing (177)Lu- or (90)Y-J591 have been reported. Long-term toxicity and chemotherapy administration was analyzed. As expected, the only serious toxicity observed was myelosuppression. Grade 4 thrombocytopenia occurred in 33.3% without significant hemorrhage and grade 4 neutropenia occurred in 17.3% with 0.07% febrile neutropenia. Nearly all subjects (97.3%) recovered to grade 0 or 1 platelets and all had complete neutrophil recovery. The majority (81.3%) received chemotherapy at any time, with 61.3% receiving chemotherapy following RIT. Ten subjects underwent bone marrow biopsies at some point in their disease course following RIT for low counts; all had diffuse PC infiltration without evidence of myelodysplasia or leukemia. As expected, myelosuppression occurs following therapeutic doses of RIT for men with metastatic castration-resistant PC. However, toxicity is predictable and self-limited, with the majority of patients who do not refuse able to receive cytotoxic chemotherapy following RIT.

Phase II study of Lutetium-177-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for metastatic castration-resistant prostate cancer.

PURPOSE: To assess the efficacy of a single infusion of radiolabeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 (lutetium-177; (177)Lu) by prostate-specific antigen (PSA) decline, measurable disease response, and survival. EXPERIMENTAL DESIGN: In this dual-center phase II study, two cohorts with progressive metastatic castration-resistant prostate cancer received one dose of (177)Lu-J591 (15 patients at 65 mCi/m(2), 17 at 70 mCi/m(2)) with radionuclide imaging. Expansion cohort (n = 15) received 70 mCi/m(2) to verify response rate and examine biomarkers. RESULTS: Forty-seven patients who progressed after hormonal therapies (55.3% also received prior chemotherapy) received (177)Lu-J591. A total of 10.6% experienced ≥50% decline in PSA, 36.2% experienced ≥30% decline, and 59.6% experienced any PSA decline following their single treatment. One of 12 with measurable disease experienced a partial radiographic response (8 with stable disease). Sites of prostate cancer metastases were targeted in 44 of 47 (93.6%) as determined by planar imaging. All experienced reversible hematologic toxicity, with grade 4 thrombocytopenia occurring in 46.8% (29.8% received platelet transfusions) without significant hemorrhage. A total of 25.5% experienced grade 4 neutropenia, with one episode of febrile neutropenia. The phase I maximum tolerated dose (70 mCi/m(2)) resulted in more 30% PSA declines (46.9% vs. 13.3%, P = 0.048) and longer survival (21.8 vs. 11.9 months, P = 0.03), but also more grade 4 hematologic toxicity and platelet transfusions. No serious nonhematologic toxicity occurred. Those with poor PSMA imaging were less likely to respond. CONCLUSION: A single dose of (177)Lu-J591 was well tolerated with reversible myelosuppression. Accurate tumor targeting and PSA responses were seen with evidence of dose response. Imaging biomarkers seem promising.

First-in-man evaluation of 2 high-affinity PSMA-avid small molecules for imaging prostate cancer.

UNLABELLED: This phase 1 study was performed to determine the pharmacokinetics and ability to visualize prostate cancer in bone, soft-tissue, and the prostate gland using (123)I-MIP-1072 and (123)I-MIP-1095, novel radiolabeled small molecules targeting prostate-specific membrane antigen. METHODS: Seven patients with a documented history of prostate cancer by histopathology or radiologic evidence of metastatic disease were intravenously administered 370 MBq (10 mCi) of (123)I-MIP-1072 and (123)I-MIP-1095 2 wk apart in a crossover trial design. (123)I-MIP-1072 was also studied in 6 healthy volunteers. Whole-body planar and SPECT/CT imaging was performed and pharmacokinetics studied over 2-3 d. Target-to-background ratios were calculated. Absorbed radiation doses were estimated using OLINDA/EXM. RESULTS: (123)I-MIP-1072 and (123)I-MIP-1095 visualized lesions in soft tissue, bone, and the prostate gland within 0.5-1 h after injection, with retention beyond 48 h. Target-to-background ratios from planar images averaged 2:1 at 1 h, 3:1 at 4-24 h, and greater than 10:1 at 4 and 24 h for SPECT/CT. Both agents cleared the blood in a biphasic manner; clearance of (123)I-MIP-1072 was approximately 5 times faster. (123)I-MIP-1072 was excreted in the urine, with 54% and 74% present by 24 and 72 h, respectively. In contrast, only 7% and 20% of (123)I-MIP-1095 had been renally excreted by 24 and 72 h, respectively. Estimated absorbed radiation doses were 0.054 versus 0.110 mGy/MBq for the kidneys and 0.024 versus 0.058 mGy/MBq for the liver, for (123)I-MIP-1072 and (123)I-MIP-1095, respectively. CONCLUSION: (123)I-MIP-1072 and (123)I-MIP-1095 detect lesions in soft tissue, bone, and the prostate gland at as early as 1-4 h. These novel radiolabeled small molecules have excellent pharmacokinetic and pharmacodynamic profiles and warrant further development as diagnostic and potentially when labeled with (131)I therapeutic radiopharmaceuticals.

Amyloid and metabolic positron emission tomography imaging of cognitively normal adults with Alzheimer's parents.

This study examines the relationship between fibrillar beta-amyloid (Aß) deposition and reduced glucose metabolism, a proxy for neuronal dysfunction, in cognitively normal (NL) individuals with a parent affected by late-onset Alzheimer's disease (AD). Forty-seven 40-80-year-old NL received positron emission tomography (PET) with (11)C-Pittsburgh compound B (PiB) and 18F-fluoro-2-deoxy-d-glucose (FDG). These included 19 NL with a maternal history (MH), 12 NL with a paternal history (PH), and 16 NL with negative family history of AD (NH). Automated regions of interest, statistical parametric mapping, voxel-wise intermodality correlations, and logistic regressions were used to examine cerebral-to-cerebellar PiB and FDG standardized uptake value ratios across groups. The MH group showed higher PiB retention and lower metabolism in AD regions compared with NH and PH, which were negatively correlated in posterior cingulate, frontal, and parieto-temporal regions (Pearson r ≤ -0.57, p ≤ 0.05). No correlations were observed in NH and PH. The combination of Aß deposition and metabolism yielded accuracy ≥ 69% for MH vs. NH and ≥ 71% for MH vs. PH, with relative risk = 1.9-5.1 (p values < 0.005). NL individuals with AD-affected mothers show co-occurring Aß increases and hypometabolism in AD-vulnerable regions, suggesting an increased risk for AD.