The preclinical evaluation of a σ receptor–specific radiopharmaceutical that binds to human prostate tumor cells with a high affinity is described. We have synthesized and radioiodinated 2-[125I]-N-(N-benzylpiperidin-4-yl)-2-iodobenzamide (2-[125I]BP) that possesses high affinity for both σ-1 and σ-2 receptor subtypes that are expressed on a variety of tumor cells. 2-IBP was synthesized, purified and characterized by routine spectroscopic and analytical methods. Radioiodination was accomplished using an oxidative iododestannylation reaction in the presence of chloramine T in high yields (76%–93%) with a very high-specific activity (1700–1900 Ci/mmol). The in vitro competition binding studies of 2-[125I]BP with various σ receptor ligands in LnCAP human prostate tumor cells showed a dose-dependent saturable binding. The inhibition constants (Ki, nM) for binding of 2-[125I]BP to human prostate tumor cells for 4-IBP, haloperidol and 2-IBP were 4.09, 6.34 and 1.6 nM, respectively. The clearance of 2-[125I]BP, in Sprague–Dawley rats, was rapid from the blood pool, other normal tissues and the total body. Tissue distribution studies in nude mice bearing human prostate tumor (DU-145) also showed a fast clearance from normal organs. The tumor had the highest percentage of injected dose per gram (%ID/g) of all tissues at 4 h as well as 24 h (2.0 ± 0.05 and 0.147 ± 0.038 ID/g, respectively) postinjection. The in vivo receptor binding specificity was demonstrated using haloperidol (a known high-affinity σ receptor ligand). A significant decrease (>50%, p = 0.001) was observed in tumor concentration when haloperidol was used as a blocking agent. The high affinity of 2-[125I]BP for σ receptor–binding sites, its fast in vivo clearance from normal organs and its high uptake and retention in tumor implies that 2-[123I]BP or 2-[131I]BP may be a promising tracer for noninvasive imaging of human prostate tumors.

Dept. of Nuclear Medicine1, Clinical Center, and Medical Branch2, Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda MD.

We prepared [125I131I]iodo-(aminostyryl)pyridinium dyes from tributylstannyl precursors. ASP 7a and 7b labeled leukocytes ex vivo (70–94%) using saline with or without washing plasma from cells. Viability of peripheral blood lymphocytes (PBLs) (dogs, rats) and splenic lymphocytes (rats) labeled with 7a and 7b (71–82%) was unchanged after labeling (⩾88%). Canine 7b-leukocytes showed higher uptake in inflammatory lesions than did 111In-oxine leukocytes. At 3 h, aspirates contained more radioiodine than 111In (1.65:1 to 22:1) and radioiodine was cell bound. ROI measurements (3 h) gave abscess to contralateral knee ratios of 12.3 and 10.6 for 131I-7b vs. 4.8 and 2.3 for 111In-oxine.

N-(2-piperidinoethyl)4-iodobenzamide), IPAB, was used to characterize sigma receptors in non-small cell lung cancer (NSCLC) cell lines. (125)IPAB bound with high affinity to large cell carcinoma (NCI-H1299), adenocarcinoma (NCI-H838), and lung carcinoid (NCI-H727) cell lines. Specific IPAB binding was inhibited with high affinity by haloperidol (Ki 0.6 nM), IPAB (Ki = 14 nM) and 1,3-ditolyl guanidine (DTG) (Ki = 40 nM). Relative to other receptor ligands, IPAB was not readily internalized at 37 degrees C. IPAB had little effect on the growth of NSCLC cells. Scintigraphic imaging studies using (131)IPAB in nude mice bearing NCI-H838 xenografts visualized the tumor at 24 or 30 hours after injection. These results suggest that sigma receptors which are present on NSCLC cells may be used as external markers for imaging tumors in vivo.

To improve the radiolabeling yield and the specific activity of [125I]N-(2-diethylaminoethyl)-4-iodobenzamide (DAB), the aryltributyltin precursor was synthesized from the N-(2-diethylaminoethyl)-4-bromobenzamide derivative by palladium catalyzed stannylation using bis(tributyltin). The radiolabeled product, [125I]DAB, was obtained by an iododestannylation reaction in high radiochemical yields (85-94%, radiochemical purity, > 98%) using chloramine-T as an oxidizing agent. The specific activity was greater than 1600 Ci/mmol. The biodistribution studies in nude mice implanted with human malignant melanoma xenograft showed a good tumor uptake (6.14% ID/g at 1 h, 2.81% ID/g at 6 h and 0.42% ID/g at 24 h) of [125I]DAB. Unfortunately, a high uptake in the non-target organs, such as liver and lung, was found. At 1 h post-injection the activity level in liver and lung was 11.76 and 7.58% ID/g, respectively. A slow clearance of activity from liver and lung was observed at 6 h (3.43 and 0.49% ID/g). These results demonstrate that iodinated IDAB is a potential radiopharmaceutical for the management of patients with malignant melanoma.

Polyclonal human IgG (IgG), antinuclear antibody (TNT-1), and human serum albumin (HSA), were labeled with 99mTc by a method recently developed in our laboratory, and administered i.v., each to a separate group of five mice, bearing inflammatory foci induced by an i.m. injection of 40μL turpentine or 5 × 108E. coli and 5 × 108 Entercocci. TNT-1 labeled with 125I served as a control and 67Ga-citrate as a “gold standard”. At 4 or 24 h post injection, animals were imaged and sacrificed for tissue distribution studies. At 4 h in the turpentine group, the abscess-to-muscle ratios were: 67Ga, 4.8 ± 2.1, 125I-TNT-1, 4.3 ± 1; 99mTc-TNT-1, 3.5 ± 1.8; 99mTc-IgG, 3.9 ± 0.6; and 99mTc-HSA, 4.3± 1. In the microorganism group, these ratios were 2.6 ± 0.6, 3.3 ± 0.5, 3.4 ± 0.08, 3± 1.1 and 4.1 ± 0.6, respectively. Autoradiographic examination of infected tissues indicated that leakage of labeled proteins into interstitial space due to increased capillary permeability may be one of the major mechanisms of uptake.

The effect of rapid converting enzyme inhibition (CEI) with intravenous enalaprilat on technetium-99m-(99mTc) diethylenetriaminepentaacetic acid (DTPA) and 99mTc-dimercaptosuccinic acid (DMSA) renograms was evaluated in rats with two-kidney, one-clip renovascular hypertension. Rapid sequential DTPA renograms, performed immediately before and five minutes after enalaprilat injection (30 micrograms/kg), demonstrated a selective decrease in clipped kidney DTPA plasma clearance following CEI and no significant effect on unclipped kidney function. Pre- and post-CEI data were obtained with a single injection of DMSA by administering enalaprilat five minutes after the radiopharmaceutical. Enalaprilat slowed the rate of DMSA accumulation in clipped relative to unclipped kidneys, and reduced the clipped/unclipped kidney ratio of absolute DMSA uptake at 10 and 30 min. DTPA and DMSA were equally effective in demonstrating the CEI effect. Enalaprilat was also compared with captopril (3 mg/kg, intraperitoneally), using sequential DTPA renograms. Clipped kidney DTPA plasma clearance was reduced to an identical degree (40%) by both converting enzyme inhibitors. Clinical renographic protocols can probably be devised to take advantage of the rapid, reliable CEI of enalaprilat, thereby shortening total procedure time.

The current role of nuclear medicine in clinical diagnosis was surveyed in a retrospective review of medical records by two internists. About one radiologic imaging study in 20 was a radionuclide procedure, and a somewhat larger fraction was performed in outpatients. The internists found that diagnostic screening procedures in nuclear medicine influenced patient management in 63% of hospital inpatients, and quantitative/monitoring types of tests influenced management in 56%. Of the projected health care costs in the United States of $490 billion, all imaging procedures will account for only $12 billion, and nuclear medicine procedures will account for about $1 billion. Nuclear medicine research continues to blossom. The National Institutes of Health budget for diagnostic imaging research in fiscal year 1988 totaled $86.6 million; nuclear medicine projects represented 43% of this total, all other projects in radiology represented 30%, and projects outside radiology represented 30%. Research with positron emitters and positron emission tomography totaled $20.5 million, and research with radiolabeled monoclonal antibodies totaled $6.2 million. Two major problems may hinder the future practice of nuclear medicine in the United States compared with that in other developed countries: (a) the serious time lag in the approval process for new radiopharmaceuticals by the U.S. Food and Drug Administration and other agencies and (b) the lack of a facility dedicated to the continuous production of radionuclides for biomedical research. Now, there is sporadic production permitted only during high-energy physics experiments. The recent developments which will probably induce the greatest changes in clinical nuclear medicine in the near future are the improvements in design and utilization of single photon emission computed tomographic devices and prolific generation of new radiopharmaceuticals, especially technetium-99m agents for cerebral and myocardial imaging and tumor agents.

Radioimmunoimaging of experimentally-induced canine thrombi has previously been achieved with iodine-131- and indium-111-labeled (131I and 111In) anti-fibrin T2G1s monoclonal antibody (MAb). We now compare T2G1s to another anti-fibrin MAb, designated GC4, for imaging fresh and aged canine thrombi. GC4 is specific for a neoepitope exposed on fibrin later in the thrombolytic process after plasmin digestion. Femoral venous thrombi were induced in six groups of dogs, each containing three dogs. In two groups, the MAbs were compared when the thrombi were 3-hr or 3-days old at the time of injection, and the dogs were killed at 48 hr. In thrombi 3-hr-old, the GC4/T2G1s concentration ratio averaged 0.53 compared to 1.9 in 3-day-old thrombi. Two groups of dogs with thrombi 1- or 3-days-old were heparinized before MAb injection and were killed at 24 hr. The heparinized dogs with thrombi 1- or 3-days-old had GC4/T2G1s mean ratios of 2.3 and 2.9, respectively. In the unheparinized groups, the corresponding ratios were 1.1 and 1.9. GC4 may be more useful for clinical thrombus imaging than T2G1s because spontaneous venous thrombi are usually several days old at the time of presentation and patients are often heparinized immediately.

HomeRadiologyVol. 171, No. 3 Next Update on radiopharmaceuticals for medical imaging.J G McAfeeJ G McAfeeJ G McAfeePublished Online:Jun 1 1989https://doi.org/10.1148/radiology.171.3.2654998MoreSectionsPDF ToolsAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookXLinked In Article HistoryPublished in print: 1989 FiguresReferencesRelatedDetailsCited BySkelettradiologieAdamGreenspan, JavierBeltran2017Use of Radiopharmaceuticals in Diagnostic Nuclear Medicine in the United StatesVladimirDrozdovitch, Aaron B.Brill, Ronald J.Callahan, Jeffrey A.Clanton, AllegraDePietro, Stanley J.Goldsmith, Bennett S.Greenspan, Milton D.Gross, Marguerite T.Hays, Stephen C.Moore, James A.Ponto, Walton W.Shreeve, Dunstana R.Melo, Martha S.Linet, Steven L.Simon2015 | Health Physics, Vol. 108, No. 5Filtration Fraction and its Implications for Radionuclide Renography Using Diethylenetriaminepentaacetic Acid and MercaptoacetyltriglycineGary F.Gates2004 | Clinical Nuclear Medicine, Vol. 29, No. 4Developments in Cardiovascular MedicineP.Galofré-Mora1994 | , Vol. 146Renal Cortical Scintigraphy and Single Proton Emission Computerized Tomography (SPECT) in the Assessment of Renal Defects in ChildrenDavid B.Joseph, Daniel W.Young, Sharon P.Jordon1990 | Journal of Urology, Vol. 144, No. 2 Part 2Recommended Articles RSNA Education Exhibits RSNA Case Collection Vol. 171, No. 3 Metrics Altmetric Score PDF download

The efficacy of five different radiodiagnostic agents for detecting renal tubular dysfunction induced with cisplatin in rats was compared to controls. Diethylenetriaminepentaacetic acid (DTPA) labeled with 99mTc or 111In was administered simultaneously with each of the other four agents [99mTc]glucoheptonate, [99mTc]dimercaptosuccinic acid, [131I]hippuran and [111In]lysozyme) as a standard to normalize for differences in functional impairment from animal to animal from the same dose of cisplatin. The 2-hr plasma clearance and computer-generated 2- to 3-min uptake in the two kidneys with [99mTc]dimercaptosuccinic acid were significantly inferior to similar measurements with the other agents in differentiating abnormal from normal function. The 2-hr uptake of [99mTc]glucoheptonate and [111In]lysozyme proved of no value in this differentiation. The late renal retention of [99mTc]dimercaptosuccinic acid well separated the cisplatin from control rats, but the greatest difference was observed by the 2-hr uptakes of [131I]hippuran and DTPA.

In Goldblatt hypertension in rats produced by implanting a silver clip on the left renal artery, captopril induces a greater difference in the 1-min uptake of diethylenetriaminepentaacetic acid (DTPA) between the two kidneys than in baseline uptakes, similar to the experiences in unilateral renovascular hypertension in man. The combination of captopril and furosemide induces an even greater difference in renal uptakes than with captopril alone in this rat model. In paired experiments, DTPA complexes were used as a standard to compare the differences in renal uptake between the two kidneys after captopril-furosemide with other existing and potential renal radiodiagnostic agents. No statistically significant difference was found between DTPA, glucoheptonate, dimercaptosuccinic acid, aminated dextran, or lysozyme. However, the differences in renal uptake were significantly less with hippuran than with DTPA. Furosemide and captopril caused delayed renal retention of hippuran after one minute. This response appeared to be due to non-specific volume depletion because it occurred in both clipped and unclipped kidneys.