肿瘤放射免疫疗法研究进展

放射免疫治疗是将针对肿瘤特异抗原的单克隆抗体用核素标记后,对肿瘤细胞进行的靶向治疗。在非霍奇金淋巴瘤的临床治疗中,放射免疫治疗已经成为一种常规的治疗手段。在实体瘤中,因为核素标记的单克隆抗体的定位很有限,所以限制了该疗法的使用。虽然如此,放射性核素标记的抗体在治疗微小病灶中的应用前景看好。     

Localization of radiolabeled anti-CEA antibody in subcutaneous and intrahepatic colorectal xenografts: influence of tumor size and location within host organ on antibody uptake

IntroductionRadioimmunotherapy (RIT) has been shown to be more effective against solid tumor micrometastases, possibly due to an inverse relationship between tumor size and radiolabeled antibody uptake. In this study, the accretion of radiolabeled antibody in intrahepatic micrometastases in an experimental model was investigated using quantitative digital autoradiography, enabling the analysis of antibody uptake in microscopic tumors.MethodsMice bearing subcutaneous or intrahepatic metastatic models of LS174T colorectal cancer were injected with radiolabeled anti-carcinoembryonic antigen antibody ([¹²⁵I]A5B7). Tissues were taken to investigate distribution of radionuclide and tumor uptake. In a therapy study, mice bearing intrahepatic metastatic tumors were injected with [¹³¹I]A5B7.ResultsSubcutaneous tumors and large metastatic deposits had similar uptake (e.g., ～15%ID/g at 24 h). Small metastatic deposits had higher uptake (e.g., ～80%ID/g at 24 h) and prolonged retention at later time points. Small deposit uptake was significantly reduced by accompanying large deposits in the same liver. RIT resulted in increased survival time (untreated mean survival of 21.6±12.9 vs. treated mean survival of 39.1±30.8 days), but there was a large range of response within groups, presumably due to variation in pattern and extent of tumor as observed in the biodistribution study. Liver function tests and body weight did not change with tumor growth or therapy response, strongly supporting the use of in vivo imaging in metastatic tumor therapy studies.ConclusionsRadioimmunodetection and therapy might be greatly influenced by the size and distribution of intrahepatic tumor deposits.     

Radioimmunotherapy of B-cell non-Hodgkin's lymphoma: from clinical trials to clinical practice.

Radioimmunotherapy (RIT) is a new treatment modality for B-cell non-Hodgkin's lymphoma (NHL). Recent clinical trials have clearly established its efficacy in NHL patients refractory to standard chemotherapy or immunotherapy with the widely used unconjugated rituximab monoclonal antibody (mAb). The Food and Drug Administration has approved (90)Y-ibritumomab tiuxetan anti-B-cell NHL mAb as the first commercially available radiolabeled antibody for cancer therapy. This comes only a few years after the introduction of rituximab into clinical practice as the first unconjugated antibody for cancer treatment, underscoring the success of both immunotherapy and RIT in the treatment of NHL. With the approval of (90)Y-ibritumomab tiuxetan, and based on the results of numerous clinical trials with radiolabeled anti-B-cell NHL mAbs, RIT promises to become integral to nuclear medicine practice. In this article, the basic concepts of RIT are reviewed with important milestones in its development for B-cell NHL treatment and particular emphasis on phase II and III clinical trials establishing its efficacy in clearly defined patient populations. Finally, the prospects for the expected widespread clinical use of RIT in the management of B-cell NHL, alone or in combination with other more established therapies, are discussed. This article provides both investigative and clinical nuclear medicine physicians with a better understanding of RIT capabilities and limitations in B-cell NHL and their role as consultants in the care of NHL patients.     

Targeted therapy of cancer with radiolabeled antibodies.

This review focuses on the use of radiolabeled antibodies in the therapy of cancer, termed radioimmunotherapy (RAIT). Basic problems concerning the choice of antibody and radionuclide and the physiology of tumor and host are discussed. Then follows a review of pertinent clinical publications on various radioantibody constructs in the treatment of hematopoietic and solid tumors of diverse histopathologies, grades, and stages, and in different clinical settings. Factors such as dose rate delivered, tumor size, and radiosensitivity play a major role in determining therapeutic response, while target-to-nontarget ratios and, particularly, circulating radioactivity to the bone marrow determine the major dose-limiting toxicities. RAIT appears to be gaining a place in the therapy of hematopoietic neoplasms, such as non-Hodgkin's lymphoma, with several agents advancing in clinical trials toward registration, of which one has just been approved by the FDA. Although RAIT of solid tumors has shown less progress, pretargeting strategies, such as an affinity-enhancement system consisting of bispecific antibodies separating targeting from delivery of the radiotherapeutic, appear to enhance tumor-to-nontumor ratios and may increase rad doses to tumor more selectively than directly labeled antibodies.     

Potentiation of radioimmunotherapy with response-selective peptide agonist of human C5a.

Physiologic barriers to the delivery of macromolecules to solid tumors are a major obstacle to the clinical success of radioimmunotherapy (RIT). Only a small fraction of the injected dose of the radiolabeled monoclonal antibody (mAb) localizes at the tumor site. This situation worsens as the tumor burden increases. It is hypothesized that improvements to RIT of adenocarcinoma can be realized by inclusion of vasoactive agents, in particular agents able to increase the vascular permeability of tumor capillaries. In these studies, a response-selective peptide agonist of human C5a, GCGYSFKPMPLaR (AP), was used to transiently increase tumor vascular permeability in an effort to improve RIT of solid tumors. METHODS: Athymic mice xenografted with human colorectal adenocarcinoma LS174T were treated intravenously with low doses (9.25 MBq) of 131I-labeled mAb B72.3 in combination with various intravenous doses of AP. The progression of the disease or the loss of >20% body weight was taken as the endpoint. Biodistribution and tumor uptake kinetics were studied in the same tumor-antibody system. RESULTS: The uptake of 125I-B72.3 in LS174T xenografts increased in a dose-dependent manner with an apparent maximal effect between 3 and 6 h after intravenous administration of AP. Augmenting the dose of 9.25 MBq 131I-B72.3 with a single administration of 0.1 mg AP delayed tumor growth nearly 2-fold; the tumor quadrupling time (T(q)) was 14.2 +/- 3.3 d for 131I-B72.3 alone versus 26.0 +/- 3.6 d for 131I-B72.3 plus 0.1 mg AP (P < 0.001). An additional dose of 0.1 mg AP 24 h after 131I-B72.3 further improved the therapeutic outcome (T(q) = 48.5 +/- 7.9 d; P < 0.001) and resulted in several cases of tumor regression. CONCLUSION: The inclusion of agonist peptides of human C5a in the RIT scheme results in improved tumor responses without any manifest side effects.     

放射性标记氨基酸的肿瘤基础研究

随着代谢显像的不断发展,放射性标记氨基酸引起临床更多关注。弄清氨基酸代谢基础和标记氨基酸在肿瘤中的作用更显必要。目前临床最常用的氨基酸显像剂如11C-蛋氨酸、11C-酪氨酸和123I-碘代甲基酪氨酸等,与18F-FDG PET相比很少受炎症影响,对脑部肿瘤显像准确性更好,对其他类型肿瘤也显示出更多的临床意义。     

Clinical characteristics of patient selection and imaging predictors of outcome in solid tumors treated with checkpoint-inhibitors

The rapidly evolving knowledge on tumor immunology and the continuous implementation of immunotherapy in cancer have recently led to the FDA and EMA approval of several checkpoint inhibitors as immunotherapic agents in clinical practice. Anti-CTLA-4, anti-PD-1, and anti-PDL-1 antibodies are becoming standard of care in advanced melanoma, as well as in relapsed or metastatic lung and kidney cancer, demonstrating higher and longer response compared to standard chemotherapy. These encouraging results have fostered the evaluation of these antibodies either alone or in combination with other therapies in several dozen clinical trials for the treatment of multiple tumor types. However, not all patients respond to immune checkpoint inhibitors, hence, specific biomarkers are necessary to guide and monitor therapy. The utility of PD-L1 expression as a biomarker has varied in different clinical trials, but, to date, no consensus has been reached on whether PD-L1 expression is an ideal marker for response and patient selection; approximately 20–25% of patients will respond to immunotherapy with checkpoint inhibitors despite a negative PD-L1 staining. On the other hand, major issues concern the evaluation of objective response in patients treated with immunotherapy. Pure morphological criteria as commonly used in solid tumors (i.e. RECIST) are not sufficient because change in size is not an early and reliable marker of tumor response to biological therapies. Thus, the scientific community has required a continuous adaptation of immune-related response criteria (irRC) to overcome the problem. In this context, metabolic information and antibody-based imaging with positron emission tomography (PET) have been investigated, providing a powerful approach for an optimal stratification of patients at staging and during the evaluation of the response to therapy. In the present review we provide an overview on the clinical characteristics of patient selection when using imaging predictors of outcome in solid tumors treated with checkpoint-inhibitors.     

Melanoma stem cells in experimental melanoma are killed by radioimmunotherapy

IntroductionIn spite of recently approved B-RAF inhibitors and immunomodulating antibodies, metastatic melanoma has poor prognosis and novel treatments are needed. Melanoma stem cells (MSC) have been implicated in the resistance of this tumor to chemotherapy. Recently we demonstrated in a Phase I clinical trial in patients with metastatic melanoma that radioimmunotherapy (RIT) with 188-Rhenium(¹⁸⁸Re)-6D2 antibody to melanin was a safe and effective modality. Here we investigated the interaction of MSC with RIT as a possible mechanism for RIT efficacy.MethodsMice bearing A2058 melanoma xenografts were treated with either 1.5 mCi ¹⁸⁸Re-6D2 antibody, saline, unlabeled 6D2 antibody or ¹⁸⁸Re-labeled non-specific IgM.ResultsOn Day 28 post-treatment the tumor size in the RIT group was 4-times less than in controls (P < 0.001). The tumors were analyzed by immunohistochemistry and FACS for two MSC markers — chemoresistance mediator ABCB5 and H3K4 demethylase JARID1B. There were no significant differences between RIT and control groups in percentage of ABCB5 or JARID1B-positive cells in the tumor population. Our results demonstrate that unlike chemotherapy, which kills tumor cells but leaves behind MSC leading to recurrence, RIT kills MSC at the same rate as the rest of tumor cells.ConclusionsThese results have two main implications for melanoma treatment and possibly other cancers. First, the susceptibility of ABCB5 + and JARID1B + cells to RIT in melanoma might be indicative of their susceptibility to antibody-targeted radiation in other cancers where they are present as well. Second, specifically targeting cancer stem cells with radiolabeled antibodies to ABCB5 or JARID1B might help to completely eradicate cancer stem cells in various cancers.     

靶向成纤维细胞活化蛋白PET显像剂的研究进展

成纤维细胞活化蛋白（FAP）在90%上皮肿瘤的肿瘤相关成纤维细胞中过表达,而在正常组织中几乎不表达,因此FAP是肿瘤诊疗的重要靶标。一系列靶向FAP的显像剂在临床前研究PET显像中展现出良好的成像结果,其表现为特异性高摄取和非靶向性低摄取。与氟脱氧葡萄糖显像相比,FAP显像在大多数恶性肿瘤中显示出更高的摄取值和灵敏性。大量的临床研究也逐步开展。靶向FAP的显像剂在多种恶性肿瘤的研究中取得了一定的进展,且有研究证实FAP在部分非肿瘤性疾病（如心肌梗死、免疫球蛋白G亚型4、结核等）中也会有高表达,因此靶向FAP的显像剂也可用于非肿瘤性疾病的诊断。笔者就靶向FAP的PET新型分子探针及其临床转化的研究进展进行综述。     

Bridged cyclams as imaging agents for chemokine receptor 4 (CXCR4)

Over-expression of chemokine receptor 4 (CXCR4) is present in a majority of cancers, has been linked to an aggressive phenotype, and may indicate the metastatic potential of primary tumor. Several CXCR4 targeted therapeutics are in clinical trials and the development of the corresponding imaging agents is an area of active interest. Previously, ⁶⁴Cu-labeled imaging agents for CXCR4 have provided clear images of CXCR4-bearing tissues in relevant experimental models but demonstrated fast washout from tissues harboring receptor. Addition of stabilizing bridges is known to provide more robust chelator-Cu(II) complexes. In addition, bridged cyclam-based CXCR4 binding agents demonstrated increased receptor residence times relative to existing agents. Based on that knowledge we synthesized several bridged cyclam analogs of AMD3465, a monocyclam-based CXCR4 imaging agent, to increase the retention time of the tracer bound to the receptor to allow for protracted imaging and improved target-to-non-target ratios. Specific accumulation of two radiolabeled, cross-bridged analogs ([⁶⁴Cu] RAD1-24 and [⁶⁴Cu]RAD1-52) was observed in U87-stb-CXCR4 tumors in both PET/CT imaging and biodistribution studies. At 90 min post-injection of radiotracer, tumor-to-muscle and tumor-to-blood ratios reached 106.05 ± 17.19 and 28.08 ± 4.78, respectively, for cross-bridged pyrimidine analog [⁶⁴Cu]RAD1-52. Receptor blockade performed in vivo denoted target binding specificity. The biodistribution and PET/CT imaging studies with the radiolabeled bridged cyclams demonstrated longer tumor retention and comparable uptake to [⁶⁴Cu]AMD3465, though [⁶⁴Cu]AMD3465 demonstrated superior overall pharmacokinetics.     

(18)F]N-(4'-fluorobenzyl)-4-(3-bromophenyl) acetamide for imaging the sigma receptor status of tumors: comparison with [(18)F]FDG, and [(125)I]IUDR

A series of biodistribution studies were conducted with the radiotracer, [(18)F]N-(4'-fluorobenzyl)-4-(3-bromophenyl)acetamide, [(18)F]1 in nude mice bearing tumor xenografts of the mouse mammary adenocarcinoma, line 66. This radiotracer has a high affinity for both sigma(1) and sigma(2) receptors. In vivo studies were also conducted in order to assess the effect of blocking sigma(1) receptors on tumor uptake and the tumor:background ratio of this radiotracer. The results of these studies revealed that blocking the sigma(1) receptor so that only the sigma(2) receptors are labeled in vivo, results in a higher tumor:background ratio with only a small reduction in the tumor uptake of the radiotracer relative to the no-carrier-added (i.e., nonselective) conditions. Comparative in vivo studies were also conducted with the anatomic and metabolic imaging agent, [(18)F]FDG, and a radiolabeled DNA precursor, [(125)I]IUdR. Both of these radiolabeled compounds represent classes of agents that have been proposed for imaging the proliferative status of solid tumors. The results of these studies indicated that a sigma(2)-selective imaging agent may be, 1) a better anatomic imaging agent for breast cancer than [(18)F]FDG, and 2) a better functional imaging agent than the radiolabeled DNA precursors, [(123/124)I]IUdR and [(11)C]thymidine, for measuring the proliferative status of breast tumors with PET and SPECT. However, additional studies will be needed to compare sigma(2)-selective imaging agents with [(18)F]FLT in order to determine which is the more appropriate imaging agent for measuring the proliferative status of breast tumors with PET.     

Clinical advantages of 3.0 T MRI over 1.5 T

Since approval by the FDA in 2000, human MR imaging (MRI) at 3.0 T has been increasingly used in clinical practice. In spite of the potential technical challenges, a number of clinical advantages of 3.0 T MRI over 1.5 T have been identified in the recent years. This article reviews the benefits and the current knowledge of 3.0 T whole-body MRI from an evidence-based perspective and summarizes its clinical applications.     

Combined treatment of advanced oropharyngeal cancer with external radiotherapy and three-step radioimmunotherapy

The prognosis of patients with locally advanced head and neck cancer remains grim due to poor locoregional tumour control. In the attempt to eradicate residual disease, various novel modalities have been tested, among which radioimmunotherapy (RIT) has shown some potential. We present a case of locally advanced oropharyngeal carcinoma successfully treated with a combination of various treatments including surgery, radio-chemotherapy and three-step RIT, with the avidin-biotin pretargeting system. A partial tumour response was achieved after surgery and radio-chemotherapy; persistent disease was documented at computed tomography (CT), ultrasound (US) and immunoscintigraphy (ISG) 10 weeks after the end of chemo-radiotherapy. The good correlation between the tracer localization in the scintigraphic images and residual mass visualized at CT suggested the application of three-step RIT using systemic administration of yttrium-90 (py) biotin. At present, 17 months after RIT, the patient is alive with no evidence of disease as documented by magnetic resonance imaging (MRI) and US. This is the first case of complete clinical remission of a head and neck carcinoma induced by combined treatment including pretargeted RIT with ⁹⁰Y-biotin. Received 15 May and in revised form 22 May 1998     

Radiolabeled peptides in diagnosis and therapy

During the past few years, there has been exponential growth in the development of radiolabeled peptides for diagnosis and therapy. This is because the peptides can be synthesized easily and inexpensively, they have fast clearance and rapid tissue penetration, and they are less likely to be immunogenic. More importantly, most peptides have a high affinity for characteristic receptor molecules that are overexpressed on malignant mammalian cells. Peptides can be labeled with a variety of radionuclides intended for specific applications, diagnostic or therapeutic, by using both conventional and novel chelating moieties, many of which can be incorporated during the solid state synthesis of a chosen peptide. High specific-activity peptides can be prepared and used to minimize unwanted physiologic effects, and known sequences of amino acids can be modified to slow their in vivo catabolic rate. These characteristics have paved the way for the preparation of a large number of radiolabeled peptides for a variety of clinical and experimental applications. This article briefly discusses the peptide chemistry; it also summarizes the preparation of radiolabeled peptides and outlines their applications in imaging vascular thrombosis, detecting infection and inflammation, and localizing tumors. Their therapeutic applications in oncology are also presented and the future directions outlined. Peptides that have been approved for human use, such as AcuTect (Diatide, Londonderry, NH) or OctreoScan (Mallinckrodt, St. Louis, MO), or those that have made it to clinical trials, are emphasized. Also discussed are selected promising agents that are still in preclinical investigation.     

Microwave accelerated labeling methods in the synthesis of radioligands for positron emission tomography imaging

Nuclear imaging using positron emission tomography [PET] is a powerful technique with clinical applications which include oncology, cardiovascular disease and CNS disorders. Conventional chemical syntheses of the short half-life radionuclides used in the process however imposes numerous limitations on scope of available ligands. By utilizing microwave assisted synthesis methods many of these limitations can be overcome, paving the way for the design of diverse families of agents with defined cellular targets. This review will survey recent developments in the field with emphasis on the period 2006-2011. Positron emission tomography [PET] has become one of the most powerful in vivo imaging modalities, capable of delivering mm3 resolution of radiotracer distribution and metabolism [1]. When combined with anatomic imaging methods (MRI, CT) co-registered multimode images offer the potential to track metabolic and physiologic events in diseased states and guide and accelerate clinical trials of investigational new drugs. Also, this same methodology can be used to evaluate first pass pharmacokinetics/pharmacodynamics in early stage drug discovery. Though powerful as a technique only a limited number of drugs have seen clinical use and to date only one drug 2-fluoro-deoxy-D-glucose (FDG) has received FDA approval [2]. One of the drawbacks of PET imaging is the need for tracers labeled with an appropriate nuclide and the half-lives of these agents places special constraints on the chemical synthesis. Among the most popular are 11C (t? =20.4 min) and 18F (t ? =109.8 min) labeled compounds and this has resulted in a resurgence of interest in practical application of their chemistries [3,4]. This review will focus on microwave mediated methods of acceleration of organic reactions used for the production of labeled PET image contrast agents, with emphasis on the five year period 2006 to 2011.     

Study of the clinical thermoluminescent dosimeter in the direct measurement of radiation absorbed dose for radioimmunotherapy

One of the major obstacles facing radioimmunotherapy (RIT) is the lack of a device to measure directly tumor and normal tissue radiation absorbed dose. Calculations based on the clearance and imaging scans have several limitations; hence we design and fabricate a sheathed clinical thermoluminescent dosimeter (TLD) for the measurement of absorbed dose by implantation in humans. Preclinical studies are performed in nine normal rabbits. Complete blood count, body temperature monitoring, clinical observation and necropsy show no untoward effects from the TLD. Consistent bone marrow radiation doses are noted in the four rabbits receiving ¹³¹I-labeled monoclonal antibody A6H. By using up to 20 clinical TLDs in one sheath, it will be possible to determine macroscopic heterogeneities in organs undergoing RIT.     

Treatment of non-Hodgkin's lymphoma (NHL) with radiolabeled antibodies (mAbs)

Most patients with non-Hodgkin's lymphoma (NHL) achieve remission but, despite newer drugs, the natural history of this disease has not improved during the last 20 years. Less than one half of patients with aggressive NHL are cured, and few of those with low-grade NHL are curable. Furthermore, NHL becomes progressively more chemoresistant while remaining responsive to external beam radiation therapy. Radioimmunotherapy (RIT) is a logical strategy for the treatment of NHL because this disease is multifocal and radiosensitive. Because of their remarkable effectiveness for RIT, 2 anti-CD20 monoclonal antibodies (mAbs), one labeled with (111)In for imaging or (90)Y for therapy and a second labeled with (131)I for imaging and therapy, have been approved for use in patients with NHL. These drugs have proven remarkably effective and safe. Evidence for the importance of the radionuclide is manifested by the data in the randomized pivotal phase III trial of (90)Y-ibritumomab that revealed response rates were several times greater in the (90)Y-ibritumomab arm than in the rituximab arm. A second drug for RIT, (131)I-tositumomab, was compared in a pivotal trial with the efficacy of the last chemotherapy received by each patient. Once again, response rates were much higher for RIT. Both (90)Y-ibritumomab and (131)I-tositumomab require preinfusion of several hundred milligrams of unlabeled anti-CD20 mAb to obtain "favorable" biodistribution, that is, targeting of NHL. Response rates for other mAbs and radionuclides in NHL also have been high but these drugs have not reached the approval stage. These drugs can be used safely by physicians who have suitable training and judgment. Unlike chemotherapy, RIT is not associated with mucositis, hair loss, or persistent nausea or vomiting. Although hematologic toxicity is dose limiting, hospitalization for febrile neutropenia is uncommon. Randomized trials of RIT in different formulations have not been conducted, but there is evidence to suggest that the mAb, antigen, radionuclide, chelator, linker, and dosing strategy may make a difference in the outcome.     

Pharmacologic intervention with angiotensin II and kininase inhibitor enhanced efficacy of radioimmunotherapy in human colon cancer xenografts.

Induced hypertension and kininase inhibition can enhance tumor targeting of radiolabeled monoclonal antibody (MAb) by altering tumor circulation. This study investigated the effect of this manipulation on the antitumor efficacy of radioimmunotherapy (RIT). METHODS: Mice bearing human colon cancer xenografts were administered 2.0 microg/kg/min of angiotensin II (AT-II) for 1 h and 30 microg of a kininase inhibitor, enalapril maleate, before the administration of 3.7 MBq (131)I-A7, an IgG1 against 45-kDa glycoprotein on colorectal cancer, and tumor growth was observed thereafter. The mechanism of the manipulation effect was investigated by estimation of the tissue absorbed dose and radioluminography of tumors. RESULTS: The pharmacologic manipulation with AT-II and enalapril improved the tumor quadrupling time (Tq) of 3.7 MBq RIT from 24.3 +/- 2.75 d to 33.1 +/- 2.83 d (P < 0.05). Addition of this manipulation made 3.7 MBq RIT as effective as 9.25 MBq RIT alone (Tq, 37.2 +/- 2.97 d). Dose estimation showed that the manipulation increased the tumor absorbed dose 1.55-fold without affecting the doses to normal tissues. Uniform intratumoral distribution in the manipulated tumors was shown by radioluminography. CONCLUSION: Larger and more uniform tumor radiation produced by this pharmacologic manipulation can benefit RIT with (131)I-MAb.     

Iodine-123-labelled fatty acids for myocardial single-photon emission tomography: current status and future perspectives

Renewed interest in the clinical use of iodine-123-labelled fatty acids is currently primarily focused on the use of iodine-123-labelled 15-(p-iodophenyl)pentadecanoic acid (IPPA) and modified fatty acid analogues such as 15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) which show delayed myocardial clearance, thus permitting single-photon emission tomographic imaging. Interest in the use of BMIPP and similar agents results from the differences which have often been observed in various types of heart disease between regional myocardial uptake patterns of [¹²³I]BMIPP and flow tracer distribution. Although the physiological basis is not completely understood, differences between regional fatty acid and flow tracer distribution may reflect alterations in important parameters of metabolism which can be useful for patient management or therapy planning. These tracers may also represent unique metabolic probes for correlation of energy substrate metabolism with regional myocardial viability. The two agents currently most widely used clinically are¹²³I-labelled IPPA and BMIPP. While [¹²³I]IPPA is commercially available as a radiopharmaceutical in Europe (Cygne) and Canada (Nordion), multicenter trials are in progress in the United States as a prelude to approval for broad use. [¹²³I]BMIPP was recently introduced as Cardiodine for commercial distribution in Japan (Nihon Medi-Physics, Inc.). [¹²³I]BMIPP is also being used in clinical studies on an institutional approval basis at several institutions in Europe and the United States. In this review, the development of a variety of radioiodinated fatty acids is discussed. The results of clinical trials with [¹²³I]IPPA and [¹²³I]BMIPP are discussed in detail, as are the future prospects for fatty acid imaging.     

Radioiodinated metaiodobenzylguanidine (MIBG): radiochemistry, biology, and pharmacology

As an analogue of adrenergic neurotransmitter norepinephrine (NE), metaiodobenzylguanidine (MIBG) demonstrates high uptake both in normal sympathetically innervated tissues, such as the heart and salivary glands, and in tumors that express the NE transporter (NET), specifically those of neural crest and neuroendocrine origin. In 1994, (131)I-MIBG, also known as iobenguane I-131 intravenous, received Food and Drug Administration (FDA) approval as an imaging agent. In 2008, (123)I-MIBG was also approved by FDA as a tumor imaging agent. Commercial formulations of radioiodinated MIBG are prepared on the basis of radioiodide exchange reaction with unlabeled MIBG as a precursor and contain large mass amounts of unlabeled MIBG, or "cold carrier," molecules. Because the cold MIBG molecules competitively inhibit the uptake of radiolabeled MIBG molecules by adrenergic and neuroendocrine cells expressing NET, no-carrier-added (n.c.a.), high specific activity (SA) radioiodinated MIBG preparations have been developed on the basis of electrophilic radioiodination reaction and solid-phase technology by using dibutylstanyl benzylguanidine precursor linked to polymers. On the basis of n.c.a. synthetic procedures, therapeutic doses of [(131)I]MIBG can be administered with very high SA (1600 mCi/μmol or 5734 mCi/mg). The very high SA of n.c.a. [(131)I]MIBG drug would increase the specific cellular uptake of adrenergic neurons and neuroendocrine tumor cells expressing NET.