Iodocholesterol adrenal tissue uptake and imaging adrenal neoplasms.

To correlate iodocholesterol tissue uptake with the ability to visualize adrenal cortical neoplasms, eight female patients with adrenal carcinoma had adrenal scintiscans after the injection of 19-[131I]iodocholesterol. Patients with cortisol-secreting carcinomas failed to image either the tumor or uninvolved adrenal tissue. In contrast, patients with androgen-secreting carcinomas (which do not suppress pituitary ACTH secretion), although still failing to image the tumor, had visible concentration of the radionuclide in the ipsilateral and contralateral adrenal glands. Slices of these tissues obtained at either surgery or postmortem examination were analyzed for iodocholesterol uptake. Results were compared with adrenal tissue obtained from patients with either cortisol- or aldosterone-secreting adenomas and patients on dexamethasone suppression. There was a strong correlation between the adrenal tissue concentration of iodocholesterol and the ability to form an image on scintiscanning. The concentration of iodocholesterol in an adenoma and a carcinoma determined in this manner was compared with their cortisol secretion during in vitro incubation. The concentration of 19-[131I]iodocholesterol and the in vitro secretion of cortisol were greater in the adenoma than in the carcinoma and corresponded with adrenal imaging in the former and lack of imaging in the latter. These data provide a quantitative assessment of the differences in radioactivity concentration required for imaging of adrenal tumors. It also demonstrates that differences in the concentration of radioactivity within adrenal carcinomas and adenomas corresponds to their ability to release cortisol in vitro.

The relationship of adrenal gland iodomethylnorcholesterol uptake to zona glomerulosa function in primary aldosteronism.

Dexamethasone suppression adrenal scintiscans were performed on 37 patients referred for evaluation of primary aldosteronism (PA). Twenty-one had aldosterone-secreting adrenal adenoma (AA) and 16 had bilateral adrenal hyperplasia (BAH). The diagnosis of either AA or BAH was confirmed by adrenalectomy in 19 of 21 subjects with AA and by adrenal venous sampling in 15 of 16 patients with BAH. Biochemical parameters of PA were found in each patient while on both high (150 meq Na) and low salt (10 meq Na) intakes. Urinary aldosterone excretion values were 49.7 +/- 10.2 (+/- SEM) micrograms/day (range, 11.2-103.9) and 44.2 +/- 12.1 micrograms/day (range, 14.3-128.0) in AA patients on high and low salt intakes, respectively. In BAH patients, urinary aldosterone values were 29.1 +/- 2.6 micrograms/day (range, 10.0-55.0) and 47.7 +/- 9.0 micrograms/day (range, 23.0-102.0) on high and low salt intakes, respectively. A semioperator-independent computer algorithm was used to calculate adrenal gland uptake of [131I]6 beta-iodomethyl-19-norcholesterol (NP-59) in PA patients and in 7 patients with essential hypertension. NP-59 adrenal uptake values were 0.20 +/- 0.02%/dose (range, 0.03-0.72), 0.28 +/- 0.04% (range, 0.10-0.65), and 0.14 +/- 0.02%/dose (range, 0.08-0.30) in AA, BAH, and essential hypertension, respectively. A significant correlation was found between adrenal gland uptake of NP-59 and urinary aldosterone excretion in AA (r = 0.93; P less than 0.001) and BAH (r = 0.6; P less than 0.01) patients. These data confirm that adrenal gland accumulation of NP-59 while on dexamethasone suppression can be used to characterize abnormal zona glomerulosa function in PA, in addition to localizing AA and differentiating AA from BAH.

The relationship of adrenal iodomethylnorcholesterol uptake to indices of adrenal cortical function in Cushing's syndrome.

The adrenal gland uptake of 131I-6-beta-iodomethyl-19-norcholesterol (NP-59) was calculated using a semioperator-independent computer algorithm in 17 patients with Cushing's syndrome (CS). Twelve had ACTH-dependent and 5 had ACTH-independent CS. The mean adrenal gland uptake (percentage of administered dose) of NP-59 was 0.74 +/- 0.18% (range, 0.21-2.02%) in CS and was significantly higher than that of normal subjects (0.33 +/- 0.02%). Patients with the ectopic ACTH syndrome and ACTH-independent CS manifested the highest uptakes (mean, 1.18 +/- 0.08%; range, 0.74-2.02%). In the patients with ACTH-dependent CS, a significant correlation was observed between 24-h urinary free cortisol excretion and NP-59 adrenal gland uptake (r = 0.97, P less than 0.001). No relationship was seen between NP-59 uptake and urinary free cortisol in ACTH-independent CS or between NP-59 uptake and urinary 17-hydroxycorticosteroids, 17-ketosteroids, cortisol secretion rate, plasma cortisol, or ACTH levels in either ACTH-dependent or ACTH-independent CS. We conclude that in addition to localizing the sites(s) of adrenocortical hypersecretion in CS, the level of NP-59 adrenal uptake is a reflection of cortisol excretion in ACTH-dependent disease and may be utilized as another parameter to quantitate adrenal disease activity in CS.

Iodine-131: optimal therapy for hyperthyroidism in children and adolescents?

To assess the medium- to long-term effects of I-131 therapy of hyperthyroidism in children and adolescents, we studied 51 patients (age range 6--18; boys, 43 girls) treated with I-131 for Graves' disease with hyperthyroidism at the University of Michigan Medical Center (1951--1972). Patients received total doses ranging from 3 to 81.6 mCi. The mean followup period was 14.6 +/- 7.9 yr. Hyperthyroidism was effectively treated in 49 within 1 to 12 mo. One patient failed to respond to three treatment doses, and hyperthyroidism recurred in two patients: 2 and 11 yr after initial therapy. Of these three patients, two were treated by thyroidectomy and one was retreated successfully with I-131. There were no cases of thyroid cancer, other malignancies or leukemia. The patients' reproductive histories and the health of their offspring were as in the general population. At the time of study, the prevalence of hypothyroidism was 92%, with no recurrent goiters or thyroid nodules. Iodine-131 is found to be safe and effective treatment of hyperthyroidism in children and adolescents and should be the preferred mode of therapy.

The normal dexamethasone-suppression adrenal scintiscan.

To establish the parameters of adrenal imaging under dexamethasone suppression (DS), 18 normotensive, normal male volunteers underwent dexamethasone-suppression adrenal scintiscanning. Five control groups were established and given dexamethasone, either 8 mg for 2 days or 4 mg for 7 days before 6 beta-[131I]iodomethyl-norcholesterol (NP-59) administration. NP-59 was given in doses of 2, 1, or 0.5 mCi. Early visualization (3--5 days) of the adrenals was noted in the groups on the 8 mg DS regimen with either 1 or 2 mCi of NP-59. Late visualization (5--7 days) was noted in the groups that received 4 mg DS and either 2, 1, or 0.5 mCi of NP-59, respectively. The normal adrenal will demonstrate uptake of NP-59 under DS, and the duration of DS before imaging is the critical factor as to when discernible adrenal visualization will occur. The documentation of the noraml suppression interval on these DS regimens provides a basis for the correct diagnostic interpretation of adrenal hyperfunction as seen on the dexamethasone-suppression NP-59 adrenal scan.

Imaging the adrenal medulla with an I-131-labeled antiadrenergic agent.

Tissue distributions of four antiadrenergic agents labeled with iodine-125 have been determined in dogs. [125I] ortho-iodobenzldimethyl-2-hydroxyethyl ammonium and [125I] ortho-iodobenzyldimethylethyl ammonium show highly selective uptake in the adrenal medulla. Studies of molecular structure-distribution indicate that both the nature of the cationic head and the ring position of the iodine atom greatly influence adrenal specificity. Distinct images of dogs' adrenal medulla have been obtained 4 days after i.v. injection of 1.5 mCi of [131I] ortho-iodobenzyldimethyl-2-hydroxyethyl ammonium.

Normal adrenal asymmetry: explanation and interpretation.

Although adrenal imaging with 19-iodocholesterol provided much useful diagnostic information, spatial resolution was less than ideal. With the greater target-to-background ratios afforded by NP-59, differences between the right and left adrenal glands--in terms of position, configuration, and depth-related activity--can now be defined. Analysis of the scintigrams of 21 individuals with no evidence of adrenal disease has allowed us to characterize the normal degree of adrenal asymmetry. Appreciation of this asymmetry is necessary if the potential for greater diagnostic accuracy afforded by NP-59 is to be realized.

Salivary gland accumulation of meta-[131I]iodobenzylguanidine.

Intense uptake of m-[131I] iodobenzylguanidine (I-131 MIBG ) has been observed in the salivary glands of patients undergoing scintigraphy for the location of suspected pheochromocytomas. This uptake of radioactivity was not due to free I-131 derived from the I-131 MIBG but rather to uptake of I-131 MIBG by sympathetic neuronal elements in the salivary glands. In keeping with this, administration of tricyclic antidepressants reversibly blocked salivary uptake of I-131 MIBG . Furthermore, I-131 MIBG uptake was markedly diminished by the ipsilateral salivary glands in a patient with Horner's syndrome, and was bilaterally diminished in a patient with severe idiopathic sympathetic autonomic neuropathy. The salivary gland uptake of I-131 MIBG may provide a means for the study of sympathetic innervation of these organs, and thus for the study of generalized disorders of autonomic innervation.

The relationship of serum lipids to adrenal-gland uptake of 6 beta-[131I]iodomethyl-19-norcholesterol in Cushing's syndrome.

An alteration in serum cholesterol levels has been suggested as a possible modifier of adrenal uptake of the cholesterol analog, 6 beta-[131I]iodomethyl-19-norcholesterol (NP-59). To assess the effect of hypercholesterolemia upon NP-59 adrenal uptake, patients with Cushing's syndrome (eight with pituitary-dependent, four with ACTH-independent, and two with ectopic-ACTH syndrome) were selected for retrospective analysis based on the availability of serum cholesterol (n = 14) and triglyceride (n = 10) concentrations obtained at the time of adrenal scintigraphy. A negative correlation (r = 0.78, p < 0.01) was found between NP-59 uptake and serum cholesterol levels in patients with pituitary-dependent Cushing's disease. Compared with pituitary-dependent disease, the ectopic-ACTH syndrome and ACTH-independent states demonstrated equal or greater adrenal uptake of NP-59 at similar serum cholesterol concentrations. Serum triglyceride concentrations did not correlate with total adrenal uptake of NP-59 in any of the patient groups studied. Increased serum cholesterol concentrations are associated with diminished adrenal uptake of NP-59, and in some cases may limit the diagnostic efficacy of adrenal scintigraphy in Cushing's syndrome.

Radiolabeled adrenergi neuron-blocking agents: adrenomedullary imaging with [131I]iodobenzylguanidine.

The tissue distributions of three radioiodinated neuron-blocking agents have been determined in dogs. Iodine-125-labeled meta- and para-iodobenzylguanidines show a striking affinity for, and retention in, the adrenal medulla. Peak concentrations of the two isomers exceed those of previously reported adrenophilic compounds. High myocardial concentrations were also observed at early time intervals. Images of the dog's adrenal medullae have been obtained with para [131I]iodobenzylguanidine.

Adrenal imaging with iodomethyl-norcholesterol (I-131) in primary aldosteronism.

Twenty consecutive patients with primary aldosteronism (PAl) underwent dexamethasone suppression (DS) imaging with 6beta-[131I]-iodomethyl-19-norcholesterol (NP-59): A) to establish the value of the adrenal scan in distinguishing aldosteronomas from bilateral hyperplasia; b) to determine its ability to locate aldosteronomas when present; and c) to compare the efficacy of NP-59 in this current series against that reported previously with NM-145 in PAl. Ten of twenty patients had an aldosteronoma, five had histologically confirmed hyperplasia, and five had presumed hyperplasia. With NP-59, nine of ten tumors were correctly located (90%) , correct distinction between tumor and hyperplasia was possible in 90%, and a locating DS scan was specific for tumor in 90%. In a combined series of different patients with PAl imaged with NM-125, 21 of 25 tumors were correctly located (84%), tumor was distinguished from hyperplasia in 86%, and the specificity of the localizing scan was 92%. The imaging delay required from tracer injection to attainment of an interpretable scan averaged 2.7 days with NP-59 and 4.8 days with NM-145. In summary, no significant differences were noted in the clinical results achieved with these two agents. The preferred agent is NP-59, since the study can be completed with less average time delay than is possible with NM-145.

Imaging the adrenal glands with radiolabeled inhibitors of enzymes: concise communication.

Although radioiodinated cholesterols furnished the first noninvasive imaging of the adrenal glands, it would be desirable to decrease the time for imaging and decrease the radiation dose. The relative tissue distributions of two radiolabeled enzyme inhibitors [3H] metyrapol and I-125-SKF-12185 were studied in dogs and man. Their percentage uptakes and target-to-nontarget ratios were similar. The adrenals of three dogs were imaged sharply at 2 hr after injection with 4--6 mCi of I-131-SKF-12185, confirmed by subsequent imaging with 1 mCi of I-131-6-beta-19-nor cholesterol at 5 days after injection. The use of 1 mCi of I-123-SKF will permit imaging of the adrenals in 1--2 hr and will decrease the radiation dose in the human to 0.76 rads to the adrenal, 0.18 rads to the ovaries and 1.7 rads to the liver.

Imaging the primate adrenal medulla with [123I] and [131I] meta-iodobenzylguanidine: concise communication.

An evaluation of radioiodinated meta-iodobenzylguanidine (m-IBG) as an adrenomedullary imaging agent is reported in 15 rhesus monkeys. Scintiscans of the monkey adrenal medulla have been obtained with [123I]- and [m-131I]IBG at 2-6 days after injection. The imaging superiority of m-IBG over its positional isomer, para-iodobenzylguanidine (p-IBG), is documented in both dogs and monkeys. Administration of reserpine, a depletor of catecholamine stores, markedly lowers the [m-131I]-IBG content of the dog adrenal medulla, but the adrenergic blocking agents phenoxybenzamine and propranolol have no effect. Subcellular fractionation of the dog's adrenal medullae reveals that m-IBG is sequestered mainly in the chromaffin storage granules. The results of this study suggest that radioiodinated m-IBG, previously reported to image the primate myocardium, also merits evaluation as a clinical radiopharmaceutical for the adrenal medulla.

Dexamethasone-suppression adrenal scintigraphy in hyperandrogenism: concise communication.

To assess the contribution of adrenal-derived androgens in women with hirsutism, adrenal scintigrams under dexamethasone suppression (DS) were performed on 35 women with increasing facial or body hair and irregular or absent menses. Based upon the DS regimen chosen (8 mg/d for 2 days or 4 mg/d for 7 days before the injection of 6 beta-[131I]iodomethylnorcholesterol), three imaging patterns were identified. The first was the absence of uptake before 3 days (8-mg DS) or before 5 days (4-mg DS) after injection. This imaging pattern was seen in 17 of the 35 patients studied and was considered normal. The second pattern was bilateral uptake earlier than 3 days (8-mg DS regimen) or 5 days (4-mg DS) after injection. This was seen in 13 of the 35 patients and was interpreted as bilateral early visualization. Adrenal-vein catheterization performed on six patients with this pattern showed increased adrenal-vein testosterone. The third pattern, observed in five patients, was unilateral early visualization, which in four cases investigated to date was the result of an adrenocortical adenoma. This study confirms the adrenal cortex as a source of androgens in women with hirsutism and hyperandrogenism and demonstrates the DS adrenal scintigraphy can be utilized to identify those women in whom adrenal-derived androgens contribute to their hyperandrogenism.

Myocardial imaging in man with I-123 meta-iodobenzylguanidine.

Meta-[123I]iodobenzylguanidine (m-[123I]IBG), a guanethidine analog, was used to image the myocardium in five normal male volunteers. Each subject received 2.0 mCi m-[123I]IBG intravenously. Four were given a bolus injection. Multiple myocardial scintigrams were obtained over a 2-hr period. Myocardial uptake was calculated by dividing the decay-corrected global myocardial count rate (after interpolated background correction) by the peak count rate during the first passage of the m-[123I]IBG bolus through the heart. The left ventricle could be visualized within 1-2 min of m-[123I]IBG injection. Mean myocardial uptake was 0.63% (range 0.45-0.78%) of injected dose at 5 min, and 0.76% (range 0.49-0.93%) at 2 hr (n = 4). m-[123I]IBG may provide quantitative information on myocardial catecholamine content.

Myocardial imaging with a radioiodinated norepinephrine storage analog.

Meta-iodobenzylguanidine (M-IBG), an iodinated aromatic analog of the hypotensive drug quanethidine, localizes in the heart of the rat, dog, and rhesus monkey. A comparative study of tissue distribution in the dog has been performed with five myocardiophilic agents: thallium-201, I-125 16-iodohexadecanoic acid, H-3 norepinephrine, C-14 guanethidine and I-125 M-IBG. The last two compounds give heart concentrations and heart-to-blood concentration ratios similar to those of thallium-201. Planar and tomographic images of the hearts of the dog and rhesus monkey were obtained using I-131 or I-123 labeled M-IBG. Blocking studies with reserpine suggest that a major component of myocardial retention of M-IBG is sequestration within the norephinephrine storage vesicles of the adrenergic nerves. The localization of M-IBG in other organs with rich sympathetic innervation and the relative insensitivity of myocardial uptake to a wide range of loading doses lend additional support for a neuronal mode of retention.

Radiopharmaceutical treatment of malignant pheochromocytoma.

Apart from relieving effects of secreted catecholamines, treatments of malignant pheochromocytoma have achieved little success. When the radiopharmaceutical, meta-[131I] iodobenzylguanidine (I-131 MIBG ), was found to concentrate in some malignant pheochromocytomas, we calculated that this agent could impart therapeutic doses of radiation to these tumors. We therefore treated five patients with two to four doses of I-131 MIBG prepared in high specific activity, 8-11 Ci/mmol. Individual doses were given at 3- to 10-mo intervals and in 97- to 197-mCi amounts. Two patients exhibited subjective and objective benefits. Their tumors declined in size (to 28% and 30% of original volumes) and in hormone secretion (to 50% or less of baseline rates). The other three patients manifested few symptoms before treatment and showed few or no objective improvement afterward. The tumors of the patients who responded to I-131 MIBG (a) appeared to be more rapidly growing, (b) received more cumulative rads, and (c) were more predominantly in soft tissues (in contrast to bone) than those in the patients who obtained little benefit. No toxic effects were encountered during the treatments, and only minor and temporary untoward responses were seen later.

Portrayal of pheochromocytoma and normal human adrenal medulla by m-[123I]iodobenzylguanidine: concise communication.

The radiopharmaceutical m-[131I]iodobenzylguanidine (I-131 MIBG), which is readily taken up by adrenergic vesicles, produces scintigraphic images of pheochromocytomas in man but rarely visualizes normal adrenal glands. Iodine-123 has many potential advantages over I-131 as a radiolabel for MIBG, including shorter half-life, freedom from beta emissions, and increased gamma-camera efficiency. In this study, diagnostic doses of MIBG labeled with I-131 and I-123, with nearly equivalent radiation dosimetry, were compared as imaging agents in eight patients with known or suspected pheochromocytoma. Images of superior quality were obtained with I-123 MIBG, and lesions not visualized using I-131 MIBG were portrayed. In addition, the normal adrenal medullae were visualized on the I-123 MIBG scintigrams in six out of eight patients.

Radiopharmaceuticals as orphan drugs.

Rare diseases and conditions are defined as diseases or conditions that affect less than 200,000 individuals in the United States. Because of the limited population suffering from any given rare disorder, there is little economic motivation for the development of drug products for its diagnosis or treatment. Also, frequently these rare diseases are misdiagnosed or undiagnosed due to a lack of familiarity with their symptoms and course. Thus, these rare disorders are commonly referred to as orphan diseases or conditions. To address this problem, legislation has been enacted that provides for incentives for the development of drug products for rare diseases or conditions (i.e., orphan drug products). Nuclear medicine scientists can take advantage of these incentives in the development of orphan radiopharmaceuticals for the treatment or diagnosis of rare diseases or conditions. Nuclear medicine physicians should know where information on orphan diseases and orphan radiopharmaceuticals can be obtained to maximize the care of their patients.

Adrenal imaging agents: rationale, synthesis, formulation and, metabolism.

In this introductory paper on radionuclide adrenal imaging, the rationale, synthesis, formulation, and metabolism of two clinically well-established and one promisinmg adrenocortical imaging agents are reviewed. Their present clinical utility is reviewed in a separate presentation in this issue. Progress to date in developing a positive imaging agent of the adrenal medulla and tumors of chromaffin tissue will be given brief consideration because there is, as yet, no clinically successful radiolabeled adrenal medulla imaging agent.