title: Radiofluorinated rhenium cyclized α-MSH analogues for PET imaging of melanocortin receptor 1.
abstract: In order to accomplish in vivo molecular imaging of melanoma biomarker melanocortin 1 receptor (MC1R), several α-melanocyte-stimulating hormone (α-MSH) analogues have been labeled with N-succinimidyl-4-¹⁸F-fluorobenzoate (¹⁸)F-SFB) and studied as positron emission tomography (PET) probes in our recent studies. To further pursue a radiofluorinated α-MSH peptide with high clinical translation potential, we utilized 4-nitrophenyl 2-¹⁸F-fluoropropionate (¹⁸F-NFP) to radiofluorinate the transition metal rhenium cyclized α-MSH metallopeptides for PET imaging of MC1R positive malignant melanoma. Metallopeptides Ac-d,Lys-ReCCMSH(Arg¹¹) (two isomers, namely RMSH-1 and RMSH-2) were synthesized using conventional solid phase peptide synthesis chemistry and rhenium cyclization reaction. The two isomers were then conjugated with ¹⁹F-NFP or ¹⁸F-NFP. The resulting cold or radiofluorinated metallopeptides, (¹⁸/¹⁹)F-FP-RMSH-1 and (¹⁸/¹⁹)F-FP-RMSH-2, were further evaluated for their in vitro receptor binding affinities, in vivo biodistribution, and small-animal PET imaging properties. The binding affinities of ¹⁹F-FP-RMSH-1 and ¹⁹F-FP-RMSH-2 were determined to be within low nanomolar range. In vivo studies revealed that both F-labeled metallopeptides possessed good tumor uptake in the B16F10 murine model with high MC1R expression, while possessing much lower uptake in A375M human melanoma xenografts. Moreover, ¹⁸F-FP-RMSH-1 displayed more favorable in vivo performance in terms of higher tumor uptake and much lower accumulation in the kidney and liver, when compared to that of ¹⁸F-FP-RMSH-2 at 2 h postinjection (p.i.). ¹⁸F-FP-RMSH-1 also displayed lower liver and lung uptake when compared with that of the same peptide labeled with ¹⁸F-SFB (named as ¹⁸F-FB-RMSH-1). Small animal PET imaging of ¹⁸F-FP-RMSH-1 in mice bearing B16F10 tumors at 1 and 2 h showed good tumor imaging quality. As expected, much lower tumor uptake and poorer tumor/normal organ contrast were observed for A375M model compared to those of the B16F10 model. ¹⁸F-FP-RMSH-1 also exhibited higher tumor uptake and better tumor retention when compared with ¹⁸F-FB-RMSH-1. ¹⁸F-FP-RMSH-1 demonstrates significant advantages over ¹⁸F-FB-RMSH-1 and ¹⁸F-FP-RMSH-2. It is a promising PET probe for imaging MC1R positive melanoma and MC1R expression in vivo.
authors.affiliation: Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Canary Center at Stanford for Cancer Early Detection, Stanford University, Stanford, California, 94305-5344, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Ren
authors.forename: Shuanlong
authors.initials: S
authors.lastname: Liu
authors.forename: Hongguang
authors.initials: H
authors.lastname: Liu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Miao
authors.forename: Zhen
authors.initials: Z
authors.lastname: Cheng
mesh_terms: D000818:Animals; D001386:Azides / Q000378:metabolism; D001565:Benzoates / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000378:metabolism; D045744:Cell Line, Tumor; D003500:Cyclization; D006801:Humans; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D008546:Melanoma, Experimental / Q000175:diagnosis / Q000000981:diagnostic imaging* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000737:chemistry; D044102:Receptor, Melanocortin, Type 1 / Q000032:analysis* / Q000378:metabolism; D012211:Rhenium / Q000737:chemistry; D012878:Skin Neoplasms / Q000175:diagnosis / Q000000981:diagnostic imaging* / Q000378:metabolism; D013388:Succinimides / Q000378:metabolism; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D000521:alpha-MSH / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D001386:Azides; D001565:Benzoates; D014408:Biomarkers, Tumor; D019275:Radiopharmaceuticals; D044102:Receptor, Melanocortin, Type 1; D013388:Succinimides; C075713:N-succinimidyl-4-fluorobenzoate; C102277:4-nitrophenyl 2-fluoropropionate; D000521:alpha-MSH; D012211:Rhenium