Multicenter validation of a shortened gastric-emptying protocol.

UNLABELLED: Gastric emptying scintigraphy is considered to be the gold standard for detection of gastroparesis and other disorders of gastric motility; Society of Nuclear Medicine and Molecular Imaging guidelines are predicated on imaging over a period of 4 h, which is inconvenient for patients. Bonta et al. introduced 2-h criteria, which served to shorten the protocol in most patients, with negligible loss of accuracy. We have evaluated the Bonta criteria in a larger multicenter trial encompassing 4 academic institutions. METHODS: Retrospective data from 4 academic medical centers were aggregated; 431 patients were included, 105 (24.4%) of whom demonstrated delayed gastric emptying defined by 4-h gastric retention of more than 10%. Bonta criteria (retention > 65% is considered abnormal and < 45% normal; otherwise, proceed to complete examination) were applied to the 2-h data. Sensitivity, specificity, accuracy, and resource use for the Bonta method were calculated. Results based on standard 4-h solid gastric emptying, performed according to current Society of Nuclear Medicine and Molecular Imaging guidelines, served as the gold standard. RESULTS: Retention of 10% or less was achieved by 6, 77, 215, and 326 patients at 1, 2, 3, and 4 h, respectively. At 2 h, 261 of 431 patients (60.6%) had gastric retention of less than 45%, which according to Bonta would be classified as normal; 62 (14.4%) had gastric retention of more than 65%, which would be classified as delayed emptying; and 108 (25.1%) had intermediate values requiring further imaging through 4 h. The Bonta criteria yielded a sensitivity, specificity, and accuracy of 92.4%, 96.9%, and 95.8%, respectively, superior to any single cutoff point applied to the 2-h values. The criteria resulted in false-negative results in 8 (1.9%) patients, 6 of whom were borderline-positive at 4 h (gastric retention of 11%-14%). Using the Bonta criteria, 74.9% of studies would be terminated by 2 h, decreasing total camera use by 15.7%, from 1,768 to 1,490 images, and the average study duration would be reduced by 20.6%, from 3.1 to 2.5 h. CONCLUSION: In a multicenter cohort, use of the Bonta criteria shortened the duration of studies in most patients, resulting in an effective compromise between reduced resource use, improved patient convenience, and preserved accuracy.

New SPECT and PET radiopharmaceuticals for imaging cardiovascular disease.

Nuclear cardiology has experienced exponential growth within the past four decades with converging capacity to diagnose and influence management of a variety of cardiovascular diseases. Single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) with technetium-99m radiotracers or thallium-201 has dominated the field; however new hardware and software designs that optimize image quality with reduced radiation exposure are fuelling a resurgence of interest at the preclinical and clinical levels to expand beyond MPI. Other imaging modalities including positron emission tomography (PET) and magnetic resonance imaging (MRI) continue to emerge as powerful players with an expanded capacity to diagnose a variety of cardiac conditions. At the forefront of this resurgence is the development of novel target vectors based on an enhanced understanding of the underlying pathophysiological process in the subcellular domain. Molecular imaging with novel radiopharmaceuticals engineered to target a specific subcellular process has the capacity to improve diagnostic accuracy and deliver enhanced prognostic information to alter management. This paper, while not comprehensive, will review the recent advancements in radiotracer development for SPECT and PET MPI, autonomic dysfunction, apoptosis, atherosclerotic plaques, metabolism, and viability. The relevant radiochemistry and preclinical and clinical development in addition to molecular imaging with emerging modalities such as cardiac MRI and PET-MR will be discussed.

Unilateral breast uptake on radionuclide ventriculography.

Gated equilibrium radionuclide ventriculography is frequently used to measure the left ventricular ejection fraction. We report a case of unilateral breast activity resulting in significant underestimation of the left ventricular ejection fraction, which mimicked a left ventricular aneurysm, pseudoaneurysm, or an intrathoracic vascular mass. Unilateral breast uptake, in the absence of gastric activity, was presumed because of increased blood pool in the lactating breast, a finding not previously reported in the literature. This case is also presented to emphasize the importance of localizing abnormalities based on a review of tomographic images or images taken in at least 2 orthogonal projections.

Metastatic ovarian carcinoma showing surprisingly widespread subcutaneous 99mTc-MDP soft-tissue uptake.

Cutaneous involvement is generally unusual for metastases in a variety of primary malignancies including patients diagnosed with ovarian cancer. We report the rare observance of subcutaneous lesions from an aggressive ovarian primary carcinoma with unusual uptake of 99mTc-MDP on a tomographic whole-body bone scan without osseous metastatic lesions or uptake. The findings were correlated with cross-sectional imaging in addition to histological analysis.

Aqueous fluoride and the preparation of [99mTc(CO)3(OH2)3]+ and 99mTc-carborane complexes.

A method for the preparation of eta5-metallocarborane complexes of technetium-99m in water was developed. The key to the procedure is the use of aqueous sodium or potassium fluoride, which prevents premature degradation of the Tc(I) starting material used to prepare the carborane complexes. Solid-phase extraction was used to purify Tc-metallocarboranes derived from both ortho and meta isomers, which were isolated in good to excellent yields in high radiochemical purities. In conjunction with these studies, a series of fluoride-based "kits" were developed to produce the key precursor [99mTc(CO)3(H2O)3]+ in the absence of any other stabilizing ligand. Using this approach, [99mTc(CO)3(H2O)3]+ could be prepared directly from 99mTcO4- under a range of pH values, including neutral pH, which affords the opportunity to develop one-pot labeling procedures for base-sensitive targeting vectors.

Synthesis of ortho- and meta-Re(I)-metallocarboranes in water.

A series of metallocarboranes of the types rac-[M(CO)3(eta(5)-7-R-7,8-C2B9H11)]-, rac-[M(CO)3(eta(5)-7-R-8-R'-7,8-C2B9H11)]-, and rac-[M(CO)3(eta(5)-7-R-7,9-C2B9H11)]- (M=Re) were prepared by reacting [NEt4]2[Re(CO)3Br3] or [Re(CO)3(OH2)3]Br with the corresponding carboranes in the presence of aqueous solutions of either alkali metal or tetraalkylammonium fluoride salts. Carborane derivatives that were investigated included those containing pyridine, amino, carboxylic acid, carbohydrate, and aryl substituents. During the course of the research, it was discovered that Re metallocarboranes can be prepared directly from the respective closo-clusters under similar reaction conditions used with nido-carboranes. Reaction yields ranged from modest to excellent depending on the carborane isomer and the nature of the cage substituent(s). A crystal structure of an amine-substituted Re metallocarborane was obtained where the complex crystallized in the orthorhombic space group P2(1)2(1)2(1) with a=8.982(2) A, b=11.563(3) A, c=16.811(4) A, alpha=beta=gamma=90 degrees, V=1746.1(7) A3, Z=4, and R1=0.0684.

A new strategy for the preparation of peptide-targeted technetium and rhenium radiopharmaceuticals. The automated solid-phase synthesis, characterization, labeling, and screening of a peptide-ligand library targeted at the formyl peptide receptor.

A new solid-phase synthetic methodology was developed that enables libraries of peptide-based Tc(I)/Re(I) radiopharmaceuticals to be prepared using a conventional automated peptide synthesizer. Through the use of a tridentate ligand derived from N-alpha-Fmoc-l-lysine, which we refer to as a single amino acid chelate (SAAC), a series of 12 novel bioconjugates [R-NH(CO)ZLF(SAAC)G, R = ethyl, isopropyl, n-propyl, tert-butyl, n-butyl, benzyl; Z = Met, Nle] that are designed to target the formyl peptide receptor (FPR) were prepared. Construction of the library was carried out in a multiwell format on an Advanced ChemTech 348 peptide synthesizer where multi-milligram quantities of each peptide were isolated in high purity without HPLC purification. After characterization, the library components were screened for their affinity for the FPR receptor using flow cytometry where the K(d) values were found to be in the low micromolar range (0.5-3.0 microM). Compound 5j was subsequently labeled with (99m)Tc(I) and the product isolated in high radiochemical yield using a simple Sep-Pak purification procedure. The retention time of the labeled compound matched that of the fully characterized Re-analogue which was prepared through the use of the same solid-phase synthesis methodology that was used to construct the library. The work reported here is a rare example of a method by which libraries of peptide-ligand conjugates and their rhenium complexes can be prepared.

Bridging the gap between in vitro and in vivo imaging: isostructural Re and 99mTc complexes for correlating fluorescence and radioimaging studies.

A bifunctional ligand that is capable of forming Re and 99mTc complexes as complementary fluorescent and radioactive probes was developed. The tridentate bis(quinoline) amine ligand, which is referred to as the SAACQ system, was prepared in a single step from Fmoc protected lysine in high yield. Reaction of the SAACQ ligand with [Re(CO)3Br3]2- resulted in the formation of the SAACQ-(Re(CO)3)+complex which exhibits favorable fluorescence properties including a long lifetime and a large Stoke's shift. Because the SAACQ ligand is derived from an amino acid, it can readily be linked to or incorporated within peptides as a means of targeting the probe to specific receptors. To demonstrate this feature, the SAACQ ligand and the SAACQ-Re complex were incorporated into fMLFG, a peptide that binds to the formyl peptide receptor (FPR). Uptake of the fMLF[(SAACQ-Re(CO)3)+]G conjugate into human leukocytes in vitro was visualized by fluorescence microscopy, and the observed distribution of the peptide was similar to that of a well-established fluorescent FPR probe. The corresponding Tc complex, fMLF[(SAACQ-99mTc(CO)3)+]G, was prepared in excellent yield from [99mTc(CO)3(OH2)3]+, which affords the opportunity to correlate the results of the microscopy experiments with in vivo radioimaging studies because the probes are isostructural.

Preparation of Re(I)- and (99m)Tc(I)-metallocarboranes in water under weakly basic reaction conditions.

A new method for the preparation of Re- and (99m)Tc-metallocarboranes in water under mild reaction conditions was developed. Three nido-carborane ligands were reacted with [Re(CO)(3)Br(3)](2)(-) in the presence of aqueous potassium fluoride to give the corresponding eta(5)-Re(CO)(3)-carborane complexes. The use of KF as a base afforded the desired Re-metallocarboranes in good yields while avoiding the formation of Re clusters, which are byproducts commonly observed when reactions are carried out in the presence of strong aqueous bases. The reaction was also performed at the tracer level producing the first (99m)Tc-carborane complex, which was isolated in 80% radiochemical yield following a simple Sep-Pak purification process. The resulting organometallic complex was stable to cysteine and histidine challenges for more than 24 h.

Synthesis, NMR, and X-ray crystallographic analysis of C-hydrazino-C-carboxycarboranes: versatile ligands for the preparation of BNCT and BNCS agents and (99m)Tc radiopharmaceuticals.

Protected hydrazine derivatives of ortho-, meta-, and para-carboranes were synthesized in good to excellent yields by reacting the mono-lithio salts of the respective carboranes with di-tert-butyl azodicarboxylate (DBAD). Subsequent deprotonation of the remaining carborane CH group, followed by the addition of CO(2)(g), resulted in the formation of bifunctional C-hydrazino-C-carboxycarboranes in good to excellent overall yields. Crystal structures of the monosubstituted ortho-carborane, 1-[(N,N'((tert-butyloxy)carbonyl)hydrazino)]-1,2-dicarba-closo-dodecaborane (8) [a = 21.213(6) A, b = 10.498(3) A, c = 9.866(2) A, alpha = gamma = 90 degrees, beta = 90.529(4) degrees ] and the bifunctional para-carborane 1-[(N,N'((tert-butyloxy)carbonyl)hydrazino)]-1,12-dicarba-closo-dodecaborane-12-carboxylic acid (3) [a = 12.744(10) A, b = 12.875(9) A, c = 14.767(9) A, alpha = beta = gamma = 90 degrees ] were obtained. Intermolecular hydrogen bonding was a dominant packing feature in both structures. The reported compounds represent a unique class of bifunctional carboranes that can be used in peptidomimetic research and as synthons to prepare novel radiopharmaceuticals and boron neutron capture therapy/boron neutron capture synovectomy (BNCT/BNCS) agents.