title: PET imaging of VPAC1 expression in experimental and spontaneous prostate cancer.
abstract: 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% +/- 2%, respectively. Inhibitory concentrations of 50% and affinity constants were 4.4 x 10(-8) M and 0.77 x 10(-9) M, respectively, for TP3939 and 9.1 x 10(-8) M and 15 x 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 +/- 3.63 %ID/g at 4 h and 5.78 +/- 0.66 %ID/g at 24 h after injection and was significantly (P < 0.05) greater than with (64)CuCl(2) (4.79 +/- 0.34 %ID/g and 4.03 +/- 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Radiology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors: Kaijun
authors: K
authors: Zhang
authors: Mohan R
authors: MR
authors: Aruva
authors: Nylla
authors: N
authors: Shanthly
authors: Christopher A
authors: CA
authors: Cardi
authors: Satish
authors: S
authors: Rattan
authors: Chirag
authors: C
authors: Patel
authors: Christopher
authors: C
authors: Kim
authors: Peter A
authors: PA
authors: McCue
authors: Eric
authors: E
authors: Wickstrom
authors: Mathew L
authors: ML
authors: Thakur
mesh_terms: D000230:Adenocarcinoma / Q000000981:diagnostic imaging / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D003301:Copper Radioisotopes; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D015609:Organotechnetium Compounds / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000096:biosynthesis*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014660:Vasoactive Intestinal Peptide / Q000031:analogs & derivatives / Q000493:pharmacokinetics
chemical_list: D003301:Copper Radioisotopes; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D014660:Vasoactive Intestinal Peptide