A stable neurotensin-based radiopharmaceutical for targeted imaging and therapy of neurotensin receptor-positive tumours.
OBJECTIVE
Neurotensin (NT) and its high affinity receptor (NTR1) are involved in several neoplastic processes. Thus, NT-based radiopharmaceuticals are potential tracers for targeted diagnosis and therapy of NTR-positive tumours. A new analogue based on NT(8-13), NT-XIX, with the three enzymatic cleavage sites stabilised, was synthesised and tested.


METHODS
The synthesis was performed by Boc strategy. Labelling with (99m)Tc/(188)Re was performed using the tricarbonyl technique. Metabolic stability was tested in vitro and in vivo. NT-XIX was further characterised in vitro in HT-29 cells and in vivo in nude mice with HT-29 xenografts.


RESULTS
NT-XIX showed much longer half-lives than non-stabilised analogues. Binding to NTR1 was highly specific, although the affinity was lower than that of natural NT. Bound activity rapidly internalised into HT-29 cells and 50% remained trapped after 24 h. In the time-course biodistribution, the highest uptake was found in the tumour at all p.i. times. In vivo uptake was specific, and accumulation of activity in the kidneys was low. Radioactivity clearance from healthy organs was faster than that from the tumour, resulting in improved tumour-to-tissue ratios and good SPECT/CT imaging. Treatment with (188)Re-NT-XIX (30 MBq, in three or four fractions) decreased tumour growth by 50% after 3 weeks.


CONCLUSIONS
The high in vivo stability and the favourable in vivo behaviour makes NT-XIX an excellent candidate for the imaging and therapy of NTR1-positive tumours.
García-Garayoa
Elisa
E
Paul Scherrer Institute, Center for Radiopharmaceutical Science, CH-5232, Villigen PSI, Switzerland. elisa.garcia@psi.ch
Bläuenstein
Peter
P
Blanc
Alain
A
Maes
Veronique
V
Tourwé
Dirk
D
Schubiger
P August
PA
D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D006207:Half-Life; D006801:Humans; D051379:Mice; D008970:Molecular Weight; D009369:Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D009496:Neurotensin / Q000737:chemistry* / Q000378:metabolism*; D015609:Organotechnetium Compounds / Q000737:chemistry; D011868:Radioisotopes / Q000737:chemistry; D019275:Radiopharmaceuticals / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018028:Receptors, Neurotensin / Q000378:metabolism*; D012211:Rhenium / Q000737:chemistry; D013194:Staining and Labeling; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
D015609:Organotechnetium Compounds; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D018028:Receptors, Neurotensin; D009496:Neurotensin; D012211:Rhenium