title: Preclinical evaluation of novel organometallic 99mTc-folate and 99mTc-pteroate radiotracers for folate receptor-positive tumour targeting.
abstract: OBJECTIVE
  The folate receptor (FR) is a valuable tumour marker, since it is frequently overexpressed on various cancer types. The purpose of the present study was to pre-clinically evaluate novel site-specifically modified (99m)Tc(CO)(3) folate (gamma-derivative 4, alpha-derivative 5) and pteroate (6) conjugates for FR targeting.
  
  
  METHODS
  The (99m)Tc(CO)(3) radiotracers 4-6 were prepared by a kit-like procedure. In vitro characterisation (K (D) and B (max)) of the radiotracers was performed with FR-positive KB cells. Tissue distribution was studied in tumour-bearing mice. SPECT/CT experiments were performed with a dedicated small animal SPECT/CT scanner.
  
  
  RESULTS
  The complexes 4-6 were formed in high yields (>92%). Binding constants of the radiotracers (K (D) in nM: 4: 2.09; 5: 2.51; 6: 14.52) were similar to those of (3)H-folic acid (K (D) in nM: 7.22). In vivo the folate derivatives showed significantly better tumour uptake (4: 2.3+/-0.4% ID/g and 5: 1.2+/-0.2% ID/g, 4 h p.i.) than the pteroate derivative (6: 0.4+/-0.2% ID/g, 4 h p.i.). Clearance of all radiotracers from the blood pool and from non-targeted tissues was efficient (tumour to blood ratio approx. 200-350, 24 h p.i.). FR-positive tissue and organs were successfully visualised via small animal SPECT/CT.
  
  
  CONCLUSIONS
  Radiotracers 4-6 are the first (99m)Tc(CO)(3) tracers prepared via a kit formulation which exhibit full biological activity in vitro and in vivo. Folate derivatives 4 and 5 revealed significantly better pharmacokinetic properties than the pteroate derivative 6. Promising pre-clinical SPECT results warrant further assessment of (99m)Tc(CO)(3) radiofolates for detection of FR-positive tumours.
authors.affiliation: Center for Radiopharmaceutical Science ETH-PSI-USZ, Paul Scherrer Institute 5232, Villigen-PSI, Switzerland.
authors.forename: Cristina
authors.initials: C
authors.lastname: Müller
authors.forename: Alexander
authors.initials: A
authors.lastname: Hohn
authors.forename: P August
authors.initials: PA
authors.lastname: Schubiger
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging* / Q000378:metabolism*; D015609:Organotechnetium Compounds / Q000737:chemistry; D011622:Pterins / Q000737:chemistry; D019275:Radiopharmaceuticals / Q000737:chemistry; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
chemical_list: D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D015609:Organotechnetium Compounds; D011622:Pterins; D019275:Radiopharmaceuticals; D011956:Receptors, Cell Surface; C517544:technetium 99m picolylamine monoacetic acid folate; C005584:pteroic acid; D005492:Folic Acid