Among U.S. men, prostate cancer (PC) accounts for 29% of all newly diagnosed cancers. A reliable scintigraphic agent to image PC and its metastatic or recurrent lesions and to determine the effectiveness of its treatment will contribute to the management of this disease. All PC overexpresses VPAC1 receptors. This investigation evaluated a probe specific for a 64 Cu-labeled receptor for PET imaging of experimental human PC in athymic nude mice and spontaneously grown PC in transgenic mice. Methods: The probe, TP3939, was synthesized, purified, and labeled with 64 Cu and 99m Tc. Using a muscle relaxivity assay, biologic activity was assessed and inhibitory concentrations of 50% calculated. Receptor affinity (Kd) for human PC3 cells was determined using 99m Tc-TP3939 and 64 CuCl 2. Blood clearance and in vivo stability were studied. After intravenous administration of either 64 Cu-TP3939 or 64 CuCl 2 in PC3 xenografts and in transgenic mice, PET/CT images were acquired. Prostate histology served as the gold standard. Organ distribution studies (percentage injected dose per gram [%ID/g]) in normal prostate were performed. The ratios of tumor to muscle, tumor to blood, normal prostate to muscle, and tumor to normal prostate were determined. Results: Chemical and radiochemical purities of TP3939 were 96.8% and 98% 6 2%, respectively. Inhibitory concentrations of 50% and affinity constants were 4.4 · 10 -8 M and 0.77 · 10 -9 M, respectively, for TP3939 and 9.1 · 10 -8 M and 15 · 10 -9 M, respectively, for vasoactive intestinal peptide 28. Binding of 64 CuCl 2 to PC3 was nonspecific. Blood clearance was rapid. In vivo transchelation of 64 Cu-TP3939 to plasma proteins was less than 15%. 64 Cu-TP3939 uptake in PC was 7.48 6 3.63 %ID/g at 4 h and 5.78 6 0.66 %ID/g at 24 h after injection and was significantly (P , 0.05) greater than with 64 CuCl 2 (4.79 6 0.34 %ID/g and 4.03 6 0.83 %ID/g at 4 and 24 h, respectively). The ratios of PC to normal prostate at 4 and 24 h were 4 and 2.7, respectively. 64 Cu-TP3939 distinctly imaged histologic grade IV prostate intraepithelial neoplasia in transgenic mice, but 18 F-FDG and CT did not. Conclusion: Data indicate that TP3939, with its uncompromised biologic activity, delineated xenografts and cases of occult PC that were not detectable with 18 F-FDG. 64 Cu-TP3939 is a promising probe for PET imaging of PC. It may also be useful for localizing recurrent lesions and for determining the effectiveness of its treatment.
Treatment of breast cancer is hampered by a large unmet need for rapid, sensitive, specific staging and stratification of palpable and nonpalpable abnormalities. Mammography and physical examination miss many early breast cancers, yet detect many benign lesions. Cyclin D1, encoded by CCND1 messenger RNA (mRNA), and insulin-like growth factor 1 receptor (IGF1R) are key regulators of cell proliferation that are overexpressed in most breast cancers. Therefore, we hypothesized that malignant breast masses could be imaged and quantitated externally by PET with a dual-specificity probe that targets both CCND1 mRNA and IGF1R. Methods: We designed a CCND1-specific peptide nucleic acid (PNA) hybridization sequence (CTGGT-GTTCCAT), separated by a C-terminal spacer to a cyclized IGF1 peptide analog (D-Cys-Ser-Lys-Cys), for IGF1R-mediated endocytosis. On the N-terminus we attached a chelator (1,4,7-tris(carboxymethylaza)cyclododecane-10-azaacetyl [DO3A]) for the positron-emitting nuclide 64 Cu. We administered the [ 64 Cu]CCND1-IGF1 analog radiohybridization probes, as well as sequence controls, by tail vein to immunocompromised female NCr mice bearing human MCF7 estrogen-dependent, receptor-positive xenografts. We imaged the mice by PET and CT 4 and 24 h later, and measured tissue distribution of the radiohybridization probes. Results: We observed 8 6 2-fold higher PET intensity in the center of the breast cancer xenografts than in the contralateral tissues at 24 h after injection of the [ 64 Cu]CCND1-IGF1 analog radiohybridization probe. IGF1 blocking yielded significantly weaker images (P , 0.05) relative to the tumor-free side at 24 h after injection, as did a PNA mismatch probe, a peptide mismatch probe, and free 64 CuCl 2 . Conclusion: These results are consistent with our hypothesis for radiohybridization PET of overexpressed CCND1 mRNA, dependent on IGF1R-mediated endocytosis, in suspect masses. Early noninvasive detection of initial cancerous transformation, as well as invasive or recurrent breast cancer, with dual-specificity radiohybridization probes, might enable molecularly targeted staging, stratification, and choice of therapy.
IntroductionVasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) receptors known as VPAC1, VPAC2 and PAC1 have been shown to be overexpressed on human tumors [1][2][3][4][5][6][7]. For these receptors, two primary peptides have high affinity [8,9]. First, the VIP, a 28-amino acid, hydrophobic peptide, isolated from porcine intestine [10]. VIP has three Lysine (Lys) residues (at positions 15, 20, and 21), two tyrosine (Tyr) residues (at positions 10 and 22), two Arginine (Arg) residues (at positions 12 and 14), an essential histidine (His) residue at the N terminus and (Asn) amidated C-terminus. All 28 amino acids are required for full biologic activity of VIP [11]. Second, the Pituitary Adenylate Cyclase Activating Polypeptide (PACAP). This 38-amino acid peptide is isolated from bovine hypothalamus [12]. PACAP was found to stimulate accumulation of intracellular and extracellular cAMP in rat anterior pituitary cells [13]. Later Gottschall et al [13] isolated a 27 amino acid peptide (PACAP 27 ) from bovine hypothalamus which they observed to have similar properties as PACAP 38 . PACAP 27 shares a homology of 19 amino acids with VIP 28 . Like VIP 28 , PACAP 27 also has an amidated (Leu) C-terminal and His at the N-terminal.The biological actions of VIP and PACAP are mediated by a family of three G protein-coupled receptors, which are designated as VPAC1, VPAC2 and PAC1 [14][15][16][17]. These gene receptors are also detected on the cell membrane of normal intestinal and bronchial epithelial cells [5,7], albeit receptor density has not been specified. For human tumors on the other hand, studies have revealed that VPAC1, VPAC2, and PAC1 receptors are located at the plasma membrane of the tumor cells [18]. Among the tumors on which VPAC1 receptors have been found in high density and high incidence, include cancers of breast, prostate and urinary bladder (100%), colon (96%), pancreas (65%), lung (58%), stomach (54%), and liver (49%) [1][2][3].With the goal that radiolabeled VIP 28 can specifically target these receptors for invivo visualization of some of these human tumors, Virgolini et al labeled VIP 28 with Iodine-123 ( 123 I) (t ½ 13.3 hr, γ=159 keV, 90%) at tyrosine position 10 and 22 [19]. Taking into consideration, the ubiquitous availability, and its predominant world wide role in nuclear medicine, we labeled VIP 28 and PACAP 27 with 99m Technetium ( 99m Tc, t½ 6 hr, γ= 140 keV, 94%) which required modification of the peptide to covalently accommodate a group of additional amino acids to chelate 99m Tc [20][21][22]. The use of 99m Tc analogues allowed efficient imaging of human breast cancer [23][24].Positron Emission Tomography (PET) permits high imaging resolution leading to the visualization of small tumors (2 mm). PET imaging of tumors with 18 Flourine ( 18 F) labeled VIP has not been highly appealing [25]. For PET imaging, our goal was to label VIP and PACAP analogues with another radionuclide, namely 64 Copper ( 64 Cu). This radionuclide has a longer half life (...
This article discusses the current techniques and future directions of infection imaging with particular attention to respiratory, CNS, abdominal, and postoperative infections. The agents currently in use localize to areas of infection and inflammation. An infection specific imaging agent would greatly improve the utility of scintigraphy in imaging occult infections. The superior spatial resolution of 18F-FDG PET and its lack of reliance on a functional immune system, gives this agent certain advantages over the other radiopharmaceuticals. In respiratory infection imaging, an important advancement would be the ability to quantitatively delineate lung inflammation, allowing one to monitor the therapeutic response in a variety of conditions. Current studies suggest PET should be considered the most accurate quantitative method. Scintigraphy has much to offer in localizing abdominal infection as well as inflammation. We may begin to see a gradual increase in the usage of FDG PET in detecting occult abdominal infections. Commonly used modalities for imaging inflammatory bowel disease are scintigraphy with 111In-oxine/99mTc-HMPAO labeled autologous white blood cells. The literature on CNS infection imaging is relatively scarce. Few clinical studies have been performed and numerous new agents have been developed for this use with varying results. Further studies are needed to more clearly delineate the future direction of this field. In evaluating the post-operative spine, 99mTc-ciprofloxacin SPECT was reported to be >80% sensitive in patients more than 6 months post-surgery. FDG PET has also been suggested for this purpose and may play a larger role than originally thought. It appears PET/CT is gaining support, especially in imaging those with fever of unknown origin or nonfunctional immune systems. While an infection specific agent is lacking, the development of one would greatly advance our ability to detect, localize, and quantify infections. Overall, imaging such an agent via SPECT/CT or PET/CT will pave the way for greater clinical reliability in the localization of infection.
Background:There are numerous methods for calculation of glomerular filtration rate (GFR), which is a crucial measurement to identify patients with renal disease.Aims:The aim of this study is to compare four different methods of GFR calculation.Settings and Design:Clinical setup, prospective study.Materials and Methods:Data was collected from routine renal scans done for voluntary kidney donors (VKD) or renal transplant recipients 6 months after transplantation. Following technetium-99m diethylene triamine penta acetic acid injection, venous blood samples were collected from contralateral arm at 120, 180, and 240 min through an indwelling venous cannula and direct collection by syringe. A total volume of 1 ml of plasma from each sample and standards were counted in an automatic gamma counter for 1 min. Blood samples taken at 120 min and 240 min were used for double plasma sample method (DPSM) and a sample taken at 180 min for single plasma sample method (SPSM). Russell's formulae for SPSM and DPSM were used for GFR estimation. Gates’ method GFR was calculated by vendor provided software. Correlation analysis was performed using Pearson's correlation test.Results:SPSM correlated well with DPSM. GFR value in healthy potential kidney donors has a significant role in the selection of donors. The mean GFR ± (standard deviation) in VKD using SPSM, DPSM, camera depth method and Cockroft Gault method was 134.6 (25.9), 137.5 (42.4), 98.6 (15.9), 83.5 (21.1) respectively. Gates’ GFR calculation did not correlate well with plasma sampling method.Conclusions:Calculation of GFR plays a vital role in the management of renal patients, hence it was noted that Gates GFR may not be a reliable method of calculation. SPSM was more reliable. DPSM is reliable but cumbersome. It is difficult to accurately calculate GFR without a gold standard.
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