Celecoxib feeding resulted in a significant decrease in prostate (56%; P < 0.0003) and genitourinary weight (48%; P < 0.008). Sequential magnetic resonance imaging analysis of celecoxib-fed mice documented lower prostate volume compared with the AIN 76A-fed group. Histopathological examination of celecoxib-fed animals showed reduced proliferation, and down-modulation of COX-2 and prostaglandin E 2 levels in the dorsolateral prostate and plasma, respectively. These results correlated with retention of antimetastasis markers, viz E-cadherin, and ␣-and ␤-catenin, along with a significant decrease in vascular endothelial growth factor protein expression. Celecoxib supplementation also resulted in enhanced in vivo apoptosis in the prostate as monitored by several techniques including a recently perfected technique of 99m Tc-labeled annexin V in live animals followed by phosphor imaging. One striking observation in an additional study was that celecoxib feeding to mice with established tumors (16 weeks of age) significantly improved their overall survival (P ‫؍‬ 0.014), compared with AIN 76A-fed group. Our findings suggest that celecoxib may be useful in chemoprevention of prostate cancer.

The alpha-melanocyte-stimulating hormone (α-MSH) receptor (melanocortin type 1 receptor, or MC1R) plays an important role in the development and growth of melanoma cells. It was found that MC1R was overexpressed on most murine and human melanoma, making it a promising molecular target for melanoma imaging and therapy. Radiolabeled α-MSH peptide and its analogs that can specifically bind with MC1R have been extensively explored for developing novel agents for melanoma detection and radionuclide therapy. The goal of this study was to evaluate a 64 Culabeled α-MSH analog, Ac-Nle-Asp-His-D-Phe-Arg-Trp-Gly-Lys(DOTA)-NH 2 (DOTANAPamide), as a potential molecular probe for microPET imaging of melanoma and MC1R expression in melanoma xenografted mouse models. 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) conjugated NAPamide was synthesized and radiolabeled with 64 Cu (t 1/2 =12 h) in NH 4 OAc (0.1 M; pH 5.5) buffered solution for 60 min at 50 °C. Cell culture studies reveal rapid and high uptake and internalization of 64 Cu-DOTA-NAPamide in B16F10 cells. Over 90% of receptor-bound tracer is internalized at 3 h incubation. A cellular retention study demonstrates that the receptor-bound 64 Cu-DOTA-NAPamide is slowly released from the B16F10 cells into the medium; 66% of the radioactivity is still associated with the cells even after 3 h incubation. The biodistribution of 64 Cu-DOTA-NAPamide was then investigated in C57BL/6 mice bearing subcutaneous murine B16F10 melanoma tumors with high capacity of MC1R and Fox Chase Scid mice bearing human A375M melanoma with a relatively low number of MC1R receptors. Tumor uptake values of 64 Cu-DOTA-NAPamide are found to be 4.63 ± 0.45% and 2.49 ± 0.31% ID/g in B16F10 and A375M xenografted melanoma at 2 h postinjection (pi), respectively. The B16F10 tumor uptake at 2 h pi is further inhibited to 2.29 ± 0.24% ID/g, while A375M tumor uptake at 2 h pi remains 2.20 ± 0.41% ID/g with a coinjection of excess α-MSH peptide. MicroPET imaging of 64 Cu-DOTA-NAPamide in B16F10 tumor mice clearly shows good tumor localization. However, low A375M tumor uptake and poor tumor to normal tissue

Melanocortin type 1 receptor (MC1R), also known as α-melanocyte–stimulating hormone (α-MSH) receptor, is an attractive molecular target for melanoma imaging and therapy. An 18F-labeled linear α-MSH peptide (18F-FB-Ac-Nle-Asp-His-D-Phe-Arg-Trp-Gly-Lys-NH2 [NAPamide]) shows promising melanoma imaging properties but with only moderate tumor uptake and retention. A transition metal rhenium-cyclized α-MSH peptide, ReO[Cys3,4,10,D-Phe7,Arg11] α-MSH3–13 (ReCCMSH(Arg11)), has shown high in vitro binding affinity to MC1R and excellent in vivo melanoma-targeting pro-files when labeled with radiometals. Therefore, we hypothesized that ReCCMSH(Arg11) could be a good platform for the further development of an 18F-labeled probe for PET of MC1R-positive malignant melanoma. Methods In this study, the metallopeptide Ac-D-Lys-ReCCMSH(Arg11) was synthesized using conventional solid-phase peptide synthesis chemistry and a rhenium cyclization reaction. The resulting peptides were then labeled with N-succinimidyl-4-18F-fluorobenzoate (18F-SFB). The 18F-labeled metallopeptides were further tested for their in vitro receptor binding affinities, in vivo biodistribution, and PET imaging properties. Results Both isomers of Ac-D-Lys-ReCCMSH(Arg11), named as RMSH-1 and RMSH-2, were purified and identified by high-performance liquid chromatography. The binding affinities of RMSH-1 and RMSH-2 and their respective 19F-SFB–conjugated peptides (19F-FB-RMSH-1 and 19F-FB-RMSH-2) were all determined to be within nanomolar range. Both 18F-labeled metallopeptides showed good tumor uptake in the B16F10 murine model, with high MC1R expression, but much lower uptake in the A375M human melanoma xenografted in mice, indicating low MC1R expression. 18F-FB-RMSH-1, when compared with 18F-FB-RMSH-2, displayed more favorable in vivo performance in terms of slightly higher tumor uptakes and much lower accumulations in the kidney and liver at 2 h after injection. Small-animal PET of 18F-FB-RMSH-1 and -2 in mice bearing B16F10 tumors at 1 and 2 h showed good tumor imaging quality. As expected, much lower tumor uptakes and poorer tumor–to–normal organ contrasts were observed for the A375M model than for the B16F10 model. 18F-FB-RMSH-1 and -2 showed higher tumor uptake and better tumor retention than did 18F-FB-NAPamide. Conclusion Specific in vivo targeting of 18F-FB-RMSH-1 to malignant melanoma was successfully achieved in preclinical models with high MC1R expression. Thus, the radiofluorinated metallopeptide 18F-FB-RMSH-1 is a promising molecular probe for PET of MC1R-positive tumors.

2′-Deoxy-2′-[ 18 F]fluoro-5-ethyl-1-β-D-arabinofuranosyluracil ([ 18 F]FEAU) is a promisingradiolabeled nucleoside designed to monitor Herpes Simplex Virus Type 1 thymidine kinase (HSV1-tk) reporter gene expression with positron emission tomography (PET). However, the challenging radiosynthesis creates problems for being able to provide [ 18 F]FEAU routinely. We have developed a routine method using a commercial GE TRACERlab FX-FN radiosynthesis module with customized equipment to provide [ 18 F]FEAU. All radiochemical yields are decay corrected to end-of-bombardment and reported as means±SD. Radiofluorination (33±8%; n=4), bromination (85±8%; n=4), coupling reaction (83±6%; n=4), base hydrolysis steps, and subsequent high-performance liquid chromatography purification afforded purified [ 18 F]FEAU β-anomer in 5±1% overall yield (n=3 runs) after ∼5.5 h and a β/α-anomer ratio of 7.4. Radiochemical/chemical purities and specific activity exceeded 99% and 1.

After purification by HPLC, the average radiochemical yield was determined to be 10-15% and the specific activity was >500 Ci/ mmol at the end of synthesis. The total synthesis time was within 60 min, and the radiochemical purity of the 18 FTPP was above 95%.