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Development of mIBG as a Cardiac Innervation Imaging Agent

University of Michigan, Ann Arbor, Michigan

Key Words: sympathetic nervous system • norepinephrine transporter • radiopharmaceuticals

Without question, the driving force behind the development of novel radiopharmaceuticals for imaging adrenal tissue at the University of Michigan was William H. Beierwaltes, MD, Chief of the Division of Nuclear Medicine, Department of Internal Medicine, from 1959 to 1986. Bill Beierwaltes was a strong and charismatic leader whose infectious enthusiasm and keen ability to establish productive collaborations were key factors in the foundation supporting the invention of mIBG at the University of Michigan.

In 1963, Dr. Beierwaltes' aspiration to develop scintigraphic imaging methods for adrenal diseases led him to recruit the medicinal chemist Raymond E. Counsell, PhD (currently Professor Emeritus of Pharmacology and Medicinal Chemistry). Their collaborative work on radiotracers for adrenal cortical diseases produced [¹³¹I]iodo-19-cholesterol (2) and its ultimate successor, 6-beta-[¹³¹I]iodomethyl-19-norcholesterol (NP-59) (3). These agents represented a significant advance in noninvasive assessments of adrenal cortical diseases; NP-59 still finds clinical use today. However, although these compounds provided scintigraphic assessments of the adrenal cortex, an important need remained for agents capable of imaging the adrenal medulla and the associated and elusive neoplasms such as pheochromocytoma and neuroblastoma.

Beierwaltes and Counsell's early efforts in this direction, reported in 1967, focused on biodistribution studies of ¹⁴C-labeled epinephrine and its precursors phenylanaline, tyrosine, DOPA, dopamine, and norepinephrine (4). Among the compounds studied, ¹⁴C-dopamine was found to have the highest adrenal medulla-to-blood ratios (740-to-1 at 6 h and 1,055-to-1 at 24 h). These important pilot studies demonstrated the feasibility of using radiolabeled catecholamine analogs as a means of concentrating an imaging agent in the storage vesicles of adrenergic tissues, a key conceptual step that set the stage for mIBG's later development.

Ray Counsell later collaborated with cardiovascular pharmacologist Benedict Lucchesi, MD, PhD, on structure-activity studies of several antiarrhythmic drugs, among them the adrenergic blocking agent bretylium. This work fostered a clinical collaboration with Edward (Ted) Carr, Jr., MD, who was interested in scintigraphic imaging of myocardial infarcts. At that time, few radiopharmaceuticals were known to concentrate in the heart, but ²⁰¹Tl was introduced for perfusion imaging in 1975 (5). Because bretylium was known to concentrate at high levels in cardiac tissue, Counsell and Carr tested a few radioiodinated analogs of bretylium as potential "myocardial scanning agents" (6). Their initial imaging studies in dogs demonstrated significant cardiac uptake of an ortho-iodo-bretylium analog called RIBA, for "radioiodinated bretylium analog" (7). However, in later searches for adrenal imaging agents, they concluded that the corresponding para-iodo-bretylium analog, p-RIBA, was better suited than RIBA for portrayal of the adrenal medulla (8).

Over the next few years, Ray Counsell's career at Michigan continued to thrive and evolve, and in 1972, he became a professor in the Department of Pharmacology, with a joint appointment in the School of Pharmacy. His departure from nuclear medicine prompted Dr. Beierwaltes to seek a radiochemist who would work full time on developing imaging agents targeting the adrenal medulla. In late 1972, Beierwaltes contacted Richard G. Lawton, PhD, a professor in Michigan's chemistry department, to ask whether he knew talented chemists who would be good candidates for an open synthetic chemist position. Dr. Lawton suggested Donald M. Wieland, PhD, a young organic chemist who had recently been hired as a lecturer in the chemistry department.

A native of Titusville, Pennsylvania, Don Wieland began his college education with the goal of becoming a high school chemistry teacher. However, after completing his education degree at Edinboro State College in 1965, Don pursued a doctoral degree in organic chemistry at West Virginia University, which he received in 1970. He moved to Detroit, Michigan, for a postdoctoral fellowship in organic chemistry at Wayne State University. It was here Don met his future wife Kathleen Taffe; Don and Kathy were married on October 23, 1970. Shortly after this, motivated by his lifelong interest in birds, Don began work on a second doctoral degree in zoology at the University of Michigan. To support his studies in Ann Arbor, Don became a lecturer in organic chemistry at Michigan.

When Don heard about the synthetic chemist position in nuclear medicine from Rich Lawton, he was intrigued, seeing it as an opportunity to merge his interests in chemistry and biology. Although Don had no formal training in radiochemistry, he was impressed by Dr. Beierwaltes' description of the project and the bright future of nuclear medicine. He quickly accepted the proffered position, joining the Division of Nuclear Medicine in December 1972.

The initial projects Don worked on were efforts to extend the promising pilot studies obtained earlier with ¹⁴C-dopamine to develop a radiopharmaceutical that would concentrate in adrenal medullary tissues. This included work on ³⁵S-labeled dopamine analogs (9) and ¹²⁵I-labeled adrenocortical enzyme inhibitors (10,11). Both of these met with limited success, and it was evident that additional approaches were required.

Looking for a new direction for adrenal imaging agents, Don reviewed Ray Counsell's published iodo-bretylium work. Don was surprised that the data from Counsell's group showed that their para-iodo-bretylium analog was more adrenospecific than the corresponding ortho-iodo analog, as ortho-substituted bretylium compounds were known to be more potent neuron blocking agents than corresponding para or meta series (12). Don felt that if the adrenal medulla could be considered a specialized sympathetic nerve ending, then the ortho-bretylium analogs should show higher localization in the adrenal medulla than the para-substitituted analogs. Don decided that a reinvestigation was warranted, so he set out to repeat Counsell's previous work and extend it to include a number of new tracers.

In early 1978, Don synthesized 5 ¹²⁵I-labeled bretylium analogs: Counsell's para- and ortho-iodo bretylium analogs (RIBA and p-RIBA), plus 3 new analogs that were arguably closer in structure to bretylium itself. Biodistribution studies clearly demonstrated that the ortho-iodo bretylium analogs had higher uptake levels in adrenal medullas than the corresponding para-iodo compounds. Furthermore, 2 of the 3 new radioiodinated bretylium analogs were superior to the RIBA compounds for imaging the adrenal medulla. The precise reasons for the discrepancies between these results and the previous studies of the RIBA compounds are unknown, but one explanation may be that the compounds in the Wieland study were prepared at more than 15-fold higher specific activity. A manuscript describing these findings was submitted in June 1978 (13), including the first scintigraphs of dog adrenal glands based on selective localization of a radiotracer in the adrenal medulla.

The demonstration that relative pharmacologic neuron blocking potency could be used to predict the degree of localization in the adrenal medulla was, in Don's estimation, an important point to establish, as it signified a rational approach to designing optimal radiotracers. Armed with the knowledge that the neuron blocking potency of compounds could be used to predict the degree of adrenomedullary uptake of their radioiodinated counterparts, Don began an extensive re-review of the literature on adrenergic neuron blocking agents, including, not only bretylium, but related compounds such as guanethidine. On a Sunday afternoon in the summer of 1978, Don was sitting in his backyard enjoying a beer and reading through a few articles he had brought home on various adrenergic neuron blocking agents. One of them was an article on the adrenergic neuron blocking activity of a series of benzylguanidines by Short and Darby (14). Included in this work were ortho- and para-iodobenzylguanidine, with the ortho-iodo derivative showing activity as an adrenergic blocking agent. Struck by the similarity in the structures of these benzylguanidines with the iodo-bretyliums he had recently worked on, Don decided to synthesize and study [¹²⁵I]ortho-iodobenzylguanidine (oIBG) and [¹²⁵I]para-iodobenzylguanidine (pIBG) as potential adrenal medulla imaging agents.

With the help of post-doctoral fellow Jiann-Long (Jeff) Wu, PhD, it took Don a few months to complete the syntheses and radiolabeling of oIBG and pIBG. Finally, in January 1979, the first biodistribution studies of ¹²⁵I-labeled oIBG and pIBG were performed in dogs. The results were somewhat surprising. The ortho-substituted analog oIBG had significantly lower uptake in adrenal medulla than para-substituted pIBG, in contrast to the previous findings with the iodo-bretylium analogs. More importantly, pIBG exhibited several-fold higher uptake levels in adrenal medulla than the best of the iodo-bretylium compounds. This exciting result stimulated a series of further animal studies of pIBG over the next few months. Also, in testament to Dr. Beierwaltes' drive and determination, only 3 months after the initial biodistribution studies in dogs, the first human studies of ¹²⁵I-pIBG were performed in 3 patients with adrenergic tumors. Pharmacokinetic data on pIBG concentrations in blood, urine, and feces were collected, in addition to measuring pIBG concentrations in the resected tumors.

Since the results with the ortho- and para-iodobenzylguanidines were opposite from what had been observed with the iodo-bretyliums, Don felt a thorough assessment of the structure-activity relationships for iodobenzylguanidines was necessary. He immediately tasked Jeff Wu with synthesizing the third possible ring-iodinated structure, mIBG. The first biodistribution studies of ¹²⁵I-mIBG were performed in April 1979, and showed comparable uptake levels with pIBG. After detailed evaluations of pIBG and mIBG in animals and human subjects, it was concluded that although pIBG had somewhat higher uptake in the adrenal medulla, mIBG, undergoing less deiodination in vivo, was more metabolically stable. Thus mIBG proved to be the optimal radioiodinated benzylguanidine for adrenomedullary imaging (15).

By October 1979, Don was increasingly aware that mIBG might be a successful cardiac sympathetic innervation imaging agent. He asked Larry Brown, a fastidious researcher responsible for all biodistribution and research imaging studies, to compile a table comparing heart-to-blood levels of iodobenzylguanidines against ²⁰¹Tl to gauge their potential as cardiac imaging agents. The data showed that mIBG had 2- to 3-fold higher heart-to-blood ratios than ²⁰¹Tl during the first hour after injection in rats, encouraging Don to investigate mIBG's ability to image the myocardium. On November 1, 1979, Don and Larry attempted the first mIBG cardiac imaging studies using ¹²³I-labeled mIBG. Two dogs were scanned in the Nuclear Medicine Clinic of the University Hospital (in the evening, after patients had left) using early single-photon tomographic techniques under investigation by W. Leslie (Les) Rogers, PhD. In each dog, cardiac uptake of ¹²³I-mIBG was clearly visualized using both 7-pinhole collimator tomography (16) and a time-modulated coded aperture system (17) (Fig. 1). This remarkably successful first experiment stimulated further cardiac imaging evaluations in dogs and primates over the next several months. However, the cardiac studies competed for resources demanded by more detailed characterizations of mIBG as an adrenal imaging agent. And with Dr. Beierwaltes' obsessive desire to bring mIBG into the clinic for adrenal imaging as soon as possible, cardiac applications of mIBG were given lower priority.

View larger version (62K): [in this window] [in a new window] [Download PPT slide]   Figure 1 Transaxial Tomographic Heart Images of the First Cardiac 123I-mIBG Study in a Dog Images were acquired using a 7-pinhole collimator (left) and coded-aperture imaging (right).

In parallel with the cardiac studies in animals, clinical evaluations of ¹²³I-mIBG uptake in normal human hearts were initiated. These pilot studies were reported in February 1981 by nuclear medicine fellow Robert Kline, MD, and faculty members in nuclear medicine and cardiology (20). This article included the first published images of ¹²³I-mIBG in human hearts.

With the demonstrated success of mIBG as a cardiac sympathetic nerve imaging agent, Don used the heart-related mIBG data to write his first National Institutes of Health grant application, with the goal of developing superior compounds for cardiac imaging. When Bill Beierwaltes learned of Don's intention to submit the application, he was, as Don recalls, less than enthusiastic. Although never stated outright, Beierwaltes likely felt that if Don became too independent, his undivided effort in continuing the work on adrenal imaging agents would be compromised. Nonetheless, Beierwaltes signed off on the grant application, which was funded by the National Heart, Lung, and Blood Institute starting in August 1981.

As one can imagine, after all the years of work that had gone into the development of a successful adrenomedullary imaging agent, pent-up demand generated a flurry of clinical studies with ¹³¹I-mIBG used to investigate various aspects of adrenal endocrinology. To meet the increasing clinical demand for mIBG, Don enlisted radiochemist Thomas J. Mangner, PhD, to help develop methods for scaling up mIBG production at higher yields and specific activities. Their efforts led to an optimized method of preparing radioiodinated mIBG using a solid-phase exchange reaction (21).

During his long and productive career, James C. Sisson, MD (Professor Emeritus of Internal Medicine), was integrally involved in most clinical mIBG studies at Michigan. Jim Sisson spent 3 months working with Dr. Beierwaltes in 1956, as a resident in internal medicine, and later joined what was then called the Radioisotope Service, as an instructor, in 1960. He collaborated with Dr. Beierwaltes and other faculty members, including Brahm Shapiro, MD, and Milton Gross, MD, on several landmark mIBG studies. Initial clinical studies demonstrated the ability of ¹³¹I-mIBG to reveal pheochromocytomas (22). This work ultimately lead to studies of ¹³¹I-mIBG as a therapeutic agent for treatment of malignant pheochromocytomas (23).

An important early observation was the inverse correlation between cardiac retention of mIBG, and plasma and urinary concentrations of catecholamines in patients with and without pheochromocytoma (24). Absence of cardiac mIBG uptake at 24 h was almost invariably seen in patients with pheochromocytomas. The article, first authored by Masayuki Nakajo, MD, a visiting fellow from Japan, was selected for a Teaching Editorial in the journal in which it appeared (25). The editorial authors accurately predicted mIBG's potential as an imaging agent for assessing the functional status of cardiac sympathetic innervation (25):

"The potential in vivo use of I-131 mIBG for studying catecholamine metabolism and for investigating adrenergic influences on the heart appears promising but remains to be explored. Certainly from the report by Nakajo et al. it seems that the effect of drugs or an adrenergic neuropathy on the catecholamine uptake mechanism may be assessed in vivo by studying the effect on heart intensity images caused by administration of I-131 mIBG."

It would take a few more years for this potential to be realized. In the meantime, studies validating the mechanisms of mIBG localization were performed. At Michigan, Michael Tobes, PhD, Sandford Jacques, Jr., PhD, and coworkers showed that the uptake and storage of mIBG closely paralleled that of the endogenous neurotransmitter norepinephrine (26,27). Further studies confirmed that the neuronal norepinephrine transporter (NET), referred to as uptake-1, was the primary mechanism responsible for mIBG uptake into cardiac sympathetic neurons (28). Nakajo, after returning to Japan, demonstrated that intraneuronal uptake of mIBG into norepinephrine storage vesicles was an important process (29).

In 1987, a seminal paper by Sisson et al. (30) described the first detailed studies of cardiac mIBG retention in human subjects. mIBG uptake and clearance rates in normal human hearts under control and pharmacological interventions were investigated, with the results strongly supporting sympathetic neurons as the locus of cardiac mIBG retention. In a few patients with generalized autonomic neuropathies (idiopathic, diabetic, and Shy-Drager syndrome), cardiac mIBG retention was reduced and nonuniform. These early findings in patients with neuropathy suggested that partial denervation could predispose patients to arrhythmias and sudden cardiac death. Moreover, the studies clearly demonstrated that mIBG scintigraphy provided clinicians with a new window into a critical component of cardiac function.

Soon after, studies in animal models of heart diseases pointed to other cardiac applications of mIBG. Mark A. Rabinovitch, MD, who had been a nuclear medicine fellow at Michigan before moving to McGill University, demonstrated that cardiac mIBG retention was significantly reduced in a canine mechanical-overload model of heart failure (31). Sisson and coworkers demonstrated that regional cardiac denervation caused by applying a phenol solution to the epicardium (which causes localized sympathetic nerve destruction) was sensitively detected by mIBG in canine hearts (32). Investigators in the laboratory of Douglas P. Zipes, MD, at Indiana University found that mIBG not only detected cardiac denervation caused by either epicardial phenol application or by transmural infarction, but also effectively tracked the subsequent reinnervation of the heart in dogs (33).

By 1988, mIBG's ability to detect cardiac sympathetic denervation was well established, and the stage was set for clinical investigators to use mIBG to explore the impact of various heart diseases on cardiac innervation. However, at Michigan, several changes to the faculty had occurred by this time that would influence the future direction of sympathetic nerve imaging at our institution. Bill Beierwaltes stepped down as Chief of the Division of Nuclear Medicine in 1986, and David E. Kuhl, MD, was recruited from the University of California, Los Angeles, to take over leadership of the Division. With Dr. Kuhl's strong background in positron emission tomography (PET), a change in emphasis from single-photon imaging techniques to PET was well under way in 1988. As part of this, Don Wieland shifted further development of sympathetic nerve radiotracers to new structures that could incorporate positron-emitting radionuclides. Initial efforts led to the development of 6-[¹⁸F]fluorometaraminol (34), and its successor, [¹¹C]meta-hydroxyephedrine (HED). Around this time, Markus Schwaiger, MD, cardiologist and nuclear medicine specialist, joined the faculty; he directed many clinical studies of cardiac sympathetic innervation using HED and PET (35). Because of this change in research directions at Michigan, most of the clinical cardiac studies with mIBG were performed at other institutions, especially at research centers in Europe and Japan.

Unfortunately, Don was stricken with Parkinson disease in 1989. Initially, the disease had little effect on his work. He next synthesized [¹¹C]epinephrine and [¹¹C]phenylephrine for PET studies of cardiac innervation (36,37). However, progression of his Parkinson disease eventually forced Don into disability leave from the University in July 2000. He is currently retired, as Professor Emeritus of Radiology. Nevertheless, he continues to follow closely our progress as we continue the development of clinically useful radiotracers in the field he pioneered. Current focus is on radiolabeled phenethylguanidines as tracers with optimal kinetics for accurately quantifying regional cardiac sympathetic nerve density (38).

In conclusion, despite the plethora of PET tracers for imaging cardiac sympathetic innervation, mIBG remains a workhorse in these vital studies. An increasing number of clinical reports point to an emerging role for sympathetic nerve imaging in cardiac patient management. The knowledge generated by these studies is providing clinicians with a greater understanding of how alterations in cardiac innervation contribute to the increased morbidity and mortality associated with many heart diseases. Thus, 30 years after the synthesis of mIBG, its pharmacokinetics and clinical applications remain highly relevant in nuclear cardiac imaging.

	Footnotes

 
Dr. Wieland is retired.

^_* Reprint requests and correspondence: Dr. David M. Raffel, Division of Nuclear Medicine, Department of Radiology, 2276 Medical Sciences I Building, University of Michigan, Ann Arbor, Michigan 48109 (Email: raffel{at}umich.edu).

Manuscript received August 21, 2009; accepted September 3, 2009.

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