title: Radioiodinated phenylalanine derivatives to image pancreatic cancer: a comparative study with [18F]fluoro-2-deoxy-D-glucose in human pancreatic carcinoma xenografts and in inflammation models.
abstract: This work validated an in vivo model of human pancreatic cancer for preclinical studies and evaluated p-amino-3-[123I]iodo-L-phenylalanine (AIPA) and p-[123I]iodo-L-phenylalanine (IPA) as potential imaging agents for pancreatic cancer. The primary human pancreatic adenocarcinoma PaCa44 and PanC1 cells (1.5-2.5x10(6)) were inoculated either subcutaneously into the flank or orthotopically into the pancreas of severe combined immunodeficient (SCID) mice. Tumor formation was recorded by palpation and monitored by magnetic resonance imaging (MRI). After intravenous injection, tumor affinity and organ distribution of AIPA and IPA were compared with those of [18F]fluoro-2-deoxy-D-glucose (FDG) in tumor-bearing SCID mice and in concanavalin A (ConA)-induced inflammation models. All SCID mice developed a pancreatic tumor 2-4 weeks after cell implantation. All subcutaneously transplanted tumors were detected by MRI and confirmed histologically, whereas 90% and 68% of the histopathologically confirmed orthotopic PaCa44 and PanC1 tumors were accurately demonstrated by MRI. Tumor formation and spread after orthotopic implantation showed invasion into adjacent organs and metastases in different sites of the abdomen. In contrast, no organ invasion or metastases were demonstrated by subcutaneous implantation. In vivo, AIPA and IPA displayed high affinity for pancreatic tumors. Radioactivity uptake into a tumor at 60 and 240 min amounted to 7.2+/-2.1% and 10.7+/-2.5% I.D./g for AIPA and 13.3+/-3.5% and 15.2+/-3.8% I.D./g for IPA in heterotopic tumors as compared with 11.8+/-3.2% and 15.2+/-2.4% I.D./g for AIPA and 16.7+/-3.5% and 22.5+/-4.3% I.D./g for IPA in orthotopically implanted tumors. In comparison, the FDG uptake was 10.8+/-2.9% and 2.5+/-0.6% I.D./g into heterotopic tumors and 12.5+/-3.8% and 3.5+/-1.2% I.D./g into the orthotopic ones at 60 and 240 min postinjection. The FDG uptake markedly increased (>400%) in the area of inflammation, whereas accumulation of AIPA and IPA in inflammation remained moderate and comparable with that determined in muscle. In summary, the orthotopic implantation model, more than the heterotopic one, reflects more closely the clinical course of the disease, thus representing the appropriate in vivo model for preclinical studies. The specific and high-level targeting of AIPA and IPA to human pancreatic tumor xenografts, with marked tumor-to-background ratios, indicate that AIPA and IPA are interesting candidates as radiotracers for noninvasive imaging of pancreatic cancer. IPA has the advantage of relatively low renal uptake and thus presents as the most promising candidate.
authors.affiliation: Department of Nuclear Medicine, Saarland University Medical Center, D-66421 Homburg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Hellwig
authors.forename: Markus
authors.initials: M
authors.lastname: Menges
authors.forename: Günther
authors.initials: G
authors.lastname: Schneider
authors.forename: Marc-Oliver
authors.initials: MO
authors.lastname: Moellers
authors.forename: Bernd F
authors.initials: BF
authors.lastname: Romeike
authors.forename: Michael D
authors.initials: MD
authors.lastname: Menger
authors.forename: Carl-Martin
authors.initials: CM
authors.lastname: Kirsch
authors.forename: Samuel
authors.initials: S
authors.lastname: Samnick
mesh_terms: D000230:Adenocarcinoma / Q000150:complications / Q000000981:diagnostic imaging / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D006801:Humans; D007249:Inflammation / Q000000981:diagnostic imaging* / Q000209:etiology / Q000378:metabolism*; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate; D051379:Mice; D016513:Mice, SCID; D009928:Organ Specificity; D010190:Pancreatic Neoplasms / Q000150:complications / Q000000981:diagnostic imaging* / Q000378:metabolism*; D010649:Phenylalanine / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
chemical_list: D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D010649:Phenylalanine