Phase-1 Clinical Trial Results of High-Specific-Activity Carrier-Free ¹²³I-Iobenguane

Abstract

A first-in-human phase 1 clinical study was performed on 12 healthy adults with a high-specific-activity carrier-free formulation of 123 Iiobenguane. Clinical data are presented on the behavior of this receptor-targeting imaging agent. Methods: Whole-body and thoracic planar and SPECT imaging were performed over 48 h for calculation of tissue radiation dosimetry and for evaluation of clinical safety and efficacy. Results: A reference clinical imaging database acquired over time for healthy men and women injected with highspecific-activity 123 I-iobenguane showed organ distribution and whole-body retention similar to those of conventional 123 I-iobenguane. The heart-to-mediastinum ratios for the high-specific-activity formulation were statistically higher than for conventional formulations, and the predicted radiation dosimetry estimations for some organs varied significantly from those based on animal distributions. Conclusion: Human normal-organ kinetics, radiation dosimetry, clinical safety, and imaging efficacy provide compelling evidence for the use of high-specific-activity 123 I-iobenguane.Key Words: iobenguane 123 I; MIBG; human dosimetry; high specific activity; human distribution J Nucl Med 2014; 55: 765-771 DOI: 10.2967/jnumed.113.124057 Iobenguane,ormet aiodobenzylguanidine (MIBG), is a guanethidine derivative functionally resembling norepinephrine. The drug guanethidine was developed in 1960 and was once a mainstay for the treatment of hypertension (1). It is no longer used in the United States; however, it is still licensed in some countries for the rapid control of blood pressure in a hypertensive emergency and as an intravenous nerve-blocking agent to treat chronic regional pain. Iobenguane and guanethidine are substrates for the norepinephrine transporter (NET) and accumulate by the uptake 1 mechanism into presynaptic nerve endings. Unlike norepinephrine, these drugs are protonated under physiologic conditions; therefore, they do not cross the blood-brain barrier and in vivo uptake is limited primarily to systemic neuronal tissue (2,3). In this paradigm, with chronic administration excess iobenguane can inhibit the neuroendocrine response in hypertensive patients, but with intravenous administration it can cause a hypertensive response often identified as iobenguane-associated adverse events.In healthy adults, the tissue density of systemic NET receptors is highest in the presynaptic neurons innervating myocytes (4). The accumulation of iobenguane in myocardial tissue is also dictated by the high fraction of aortic blood flow that enters the coronary arteries. This physiology constitutes an ideal molecular targeting mechanism for diagnosis of various cardiac diseases, including heart failure, heart transplant rejection, ischemic heart disease, dysautonomia, and drug-induced cardiotoxicity, as well as cardiac neuropathy related to diabetes mellitus and Parkinson disease (5-7). If a substantial fraction of the receptors are occupied by nonradioactive substrates, the overall uptake of radioactiv...

Norepinephrine Transporter as a Target for Imaging and Therapy

“…It is more specific than MRI and has replaced bone scanning in routine evaluation (11)(12)(13). The reported sensitivity of 123 I-or 131 I-MIBG for staging or recurrent neuroblastoma ranges from 76% to 100% (14)(15)(16). A prospective multicenter trial reported sensitivity of 88% and specificity of 83% for detection at diagnosis or follow-up (17).…”

“…A prospective multicenter trial reported sensitivity of 88% and specificity of 83% for detection at diagnosis or follow-up (17). 123 I-MIBG is reported to detect 82% of unsuspected relapses, including 27% that were otherwise undetected by other modalities (18).…”

“…131 I/ 123 I-MIBG is widely used for imaging neuroblastoma and is considered the gold standard for staging and follow-up of neuroblastoma patients (10,11). Although initially 131 I-MIBG was used for imaging, it has been replaced to a large extent by 123 I-MIBG, which, even though more expensive, is more favorable due to its shorter half-life and lower radiation dose that allows for higher injected activity and for superior quality of both planar and SPECT imaging.…”

“…Most of the iodine localizes intracellularly within the mitochondria, and lesser amounts are seen in the vesicles and nuclear membrane. The decay characteristics of 131 I-with emissions of energy that allow for penetration in the nucleus-make it suitable for therapy (9), whereas the lower g-energy of 123 I makes it a preferred isotope for imaging. 131 I/ 123 I-MIBG is widely used for imaging neuroblastoma and is considered the gold standard for staging and follow-up of neuroblastoma patients (10,11).…”

“…The uptake in the tumor is proportional to the number of neurosecretory granules (7), which may result in variable uptake and detection of tumor. MIBG radiolabeled with 131 I or 123 I has been used for targeted imaging with a g-scanner for planar imaging and SPECT imaging, whereas 131 I-MIBG has been used for therapy of neuroendocrine tumors.…”