Ronald E. Weiner

Radiolabeled peptides in the diagnosis and therapy of oncological diseases

There has been an exponential growth in the development of radiolabeled peptides for diagnostic and therapeutic applications in oncology. Peptides have fast clearance, rapid tissue penetration, low antigenicity and can be produced easily and inexpensively. However, peptides have problems with in vivo catabolism, unwanted physiological effects, and chelate attachment. The approved 111In-DTPA-OctreoScan, a somatostatin receptor binder, is well established for diagnosis of neuroendocrine tumors. NeoTect, an approved, 99mTc-labeled, somatostatin-receptor-binding analogue has good specificity for lung cancer detection. The receptors for Vasoactive Intestinal Peptide, Cholecystokinin-B/gastrin, Bombesin, Epidermal Growth Factor, and Alpha Melanocyte Stimulating Hormone and the Integrin, alpha(v)beta(3), are under active investigation as targets. Octreotide and its analogues labeled with 111In, 90Y, 64Cu or 177Lu are under study for the treatment of patients with promising results.

Radiolabeled Peptides in Oncology

There has been an exponential growth in the development of radiolabeled peptides for diagnostic and therapeutic applications in the last decade. The automated means of synthesizing these compounds in large quantities and the simplified methods of purifying, characterizing, and optimizing them have kindled attention to peptides as carrier molecules. These new techniques have accelerated the commercial development of radiolabelled peptides, which has provided additional radiopharmaceuticals for the nuclear medicine community.Peptides have many key properties including fast clearance, rapid tissue penetration, and low antigenicity, and can be produced easily and inexpensively. However, there may be problems with in vivo catabolism, unwanted physiologic effects, and chelate attachment. Radiolabeled peptides have made their greatest impact in the management of relatively rare neuroendocrine malignancies. Indeed, Indium-111 (111In)-pentetreotide (111In-DTPA-octreotide, Octreoscan®), which binds to somatostatin receptors (SSTRs), has become the diagnostic ‘gold standard’ in these diseases. However, 111In-pentetreotide has been less successful in the diagnosis of other more prevalent diseases in which SSTRs are upregulated. Technetium-99m (99mTc)-depreotide (NeoTect™), a 99mTc-labeled SSTR-analog, could have wider impact since it has high sensitivity and specificity for lung cancer lesion detection. However, this impact may be minimized by the increased availability of positron emission tomography imaging with Fluorine-18 (18F)-flourodeoxyglucose, which has similar sensitivity and specificity for lesion identification in this disease, and is currently more widely used. The receptors for bombesin, α-melanocyte-stimulating hormone, neurotensin, and the integrin αvβ3, are under active investigation as targets for radiolabelled peptides, but are still in the pre-clinical stage. Compounds directed at the cholecystokinin-B/gastrin receptor have shown promising results in clinical trials in humans.Radiolabelled peptide therapy is usually indicated for patients with widespread disease that is not amenable to focused radiation therapy or is refractory to chemotherapy. Phase I/II studies using various radiolabelled peptides (including 111In-pentetreotide, Yttrium-90 [90Y]-DOTA-Phe1-Tyr3-octreotide, 90Y-DOTA-lanreotide, and Lutetium-177 [177Lu]-DOTA-octreotate) for the treatment of patients with neuroendocrine malignancy are in progress. Over 400 patients have been treated, and the response rate has ranged from 60% to 75%, although few patients have had a complete response. Patients have been given individual doses ranging from 2 to 11 GBq with a slow infusion every 4–8 weeks (up to 12 times). The kidney is the dose-limiting organ and most patients experience a transient decline in blood cell counts. A concomitant infusion of an amino acid mixture can reduce kidney toxicity and increase the effective tumor dose. Other peptides currently under investigation, some of which have shown promising results, include Rhenium-188 (188Re)-P2045 and 90Y-αvβ3 antagonist.

Dietary arginine alters time of symptom onset in Huntington's disease transgenic mice.

Recent neuroimaging studies reported complex changes in cerebral blood flow (CBF) in early-staged Huntingtons disease (HD) patients. Deckel and co-workers [Deckel and Duffy, Brain Res. (in press); Deckel and Cohen, Prog. Neuro-Psychopharmacol. Biol. Psychiatry 24 (2000) 193; Deckel et al., Neurology 51 (1998) 1576; Deckel et al., J. Nucl. Med. 41 (2000) 773] suggested that these findings might be accounted for, in part, by alterations in cerebral nitric oxide (NO) and its byproduct, peroxynitrite. The current experiment tested this hypothesis by altering NO levels via manipulations of dietary L-arginine (ARG), the dietary precursor of NO, in mice transgenic for HD. Seventy-one mice were assigned at 12 weeks of age to one of three isocaloric diets that varied in their content of ARG. These diets included: (a) 0% ARG, (b) 1.2% ARG (i.e. typical mouse chow), or (c) 5% ARG. The 5% ARG diets in HD mice accelerated the time of onset of body weight loss (P<0.05) and motor impairments (P<0.05), and increased resting CBF in HD relative to control (P<0.05). Conversely, the 0% ARG diet demonstrated no loss of body weight and had no changes in CBF relative to controls. However, the 0% ARG HD group continued to show significant deficits on motor testing (P<0. 05). The 1.2% ARG HD group showed reduced body weight loss, better motor functioning, and fewer changes in CBF compared to the 5% ARG HD group. Immunocytochemistry analysis found greater deposition of nitrotyrosine in the cortex, and vasculature, of HD+ mice, 5% and 1. 2%>0% arginine diets. When collapsed across all conditions, CBF inversely correlated (P<0.05) both with the body weight and motor changes suggesting that changes in CBF are associated with behavioral decline in HD mice. Collectively, these findings indicate that dietary consumption of the NO precursor ARG has a measurable, but complex, effect on symptom progression in HD transgenic mice, and implicates NO in the pathophysiology of HD.

The role of transferrin and other receptors in the mechanism of 67Ga localization

Gallium-67 is a useful adjunct in the diagnosis of a variety of diseases. At present 67Ga is the radiopharmaceutical of choice for radionuclide imaging of tumors and can be used to monitor the efficacy of a particular therapeutic regimen (Bekerman et al., 1985). Clinical studies have shown the utility of 67Ga in a number of neoplastic diseases; Hodgkin’s disease, histiocytic lymphoma, lung cancer, hepatoma and melanoma. It is also used for infections of lung, e.g. P. carinii pneumonia, abdomen, bone, joints and kidneys and for the detection of occult inflammation. Whereas the sensitivity of this technique is always very high, 90-95%, the specificity is generally low because 67Ga can concentrate in both tumors and inflammatory processes. With additional clinical information the specificity can usually be improved to 80-90% range. Other drawbacks include nonspecific, high liver and bowel uptake (obscuring liver and bowel lesions) and long time intervals before imaging (2448 h). In particular, because bowel activity may present as a problem, the “‘In labeled white blood cells technique (“‘In-WBC) will likely replace 67Ga imaging for abdominal lesions (Goodwin et al., 1981). In the detection of chronic inflammations, however, data from human (Sfakianakis et al., 1982) and animal (Bitar et al., 1986) studies suggest that 67Ga may be superior to “‘In-WBC. Also a recent clinical study using both a “‘In-antimelanoma monoclonal antibody and 67Ga showed that the agents were complementary combining to increase sensitivity (Cornelius et al., 1986). This suggests that 67Ga will remain a viable technique, at least in the near future. To attempt to improve the 67Ga imaging technique there have been numerous investigations into the localization mechanism. Although in nuclear medicine the latest buzzword is receptors, many fail to think of “‘Ga localization as a receptor-mediated process, probably because of the conflicting data. Previous reviews have discussed the factors involved in 67Ga localization (Hoffer, 1980; Tsan, 1985; Tsan and Scheffel, 1986). In this review I wish to specifically examine the conflicting evidence concerning the role of transferrin and other receptors in 67Ga uptake. In addition, this will be placed in a historical perspective summarizing earlier work and examining in detail the most recent data.

Quantification of gallium-67 citrate in breast milk

A woman, 6 months postpartum and nursing her child, had a Ga-67 scintigram. A sample of breast milk obtained at day 2 revealed 2.8% of the injected dose (ID) per liter. The percent ID/L was compared with literature values; the highest concentration was in a report of galactorrhea. Similarity of the gallate ion to phosphate, as a possible explanation for accumulation in the breast, was pointed out. An earlier recommendation that a patient given Ga-67 citrate should discontinue breast feeding for at least 2 weeks was re-examined.

The Future of USP Monographs for PET Drugs

1Washington University School of Medicine, St. Louis, Missouri; 2Committee on Pharmacopeia, Society of Nuclear Medicine and Molecular Imaging, Reston, Virginia; 3University of New Mexico Health Sciences Center, Albuquerque, New Mexico; 43D Imaging, LLC, University of Arkansas for Medical Sciences, Little Rock, Arkansas; 5Beth Israel Deaconess Medical Center, Boston, Massachusetts; 6Mayo Clinic, Rochester, Minnesota; 7University of Washington, Seattle, Washington; 8Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsyvania; 9Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts; 10Brigham and Women’s Hospital, Boston, Massachusetts; 11Duke University Medical Center, Durham, North Carolina; 12University of Iowa, Iowa City, Iowa; 13Seifert and Associates, Los Angeles, California; 14University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania; 15Ron Weiner Services, Sherman Oaks, California; and 16Siemens PETNET Solutions, Knoxville, Tennessee

Photopenic to Avid Radiogallium Transition after Rupture of the Marrow Cavity in Acute Femoral Osteomyelitis

A 4-year-old boy had markedly reduced Ga-67 uptake in a painful left leg when compared with the right. A repeat study 9 days later showed an intense accumulation of nuclide in the lower left femur and surrounding area. Increased intramedullary pressure probably precluded Initial Ga-67 delivery into the site of infection, and subsequent release of this pressure permitted accumulation.