Aim. To date there is no minigastrin analogue suitable for targeted molecular radiotherapy of medullary thyroid carcinoma and other gastrin receptor expressing tumors. The drawback of current targeting agents is either their metabolic instability or their high kidney retention, limiting the maximum activity that can be administered without the induction of radiation nephrotoxicity. Till now high kidney retention of minigastrin analogues has been related to the N-terminal glutamic acids and could be substantially reduced by coinjection of polyglutamic acids or the gelatin-based plasma expander gelofusine. The aim of this study was to investigate the influence of stereochemistry of amino acid spacer, namely (L-Glu)6 vs. (D-Glu)6 on metabolic stability and pharmacokinetics of 111In-DOTA-minigastrin analogues. Materials and Methods. Both DOTA coupled peptides were synthesized manually on solid phase using Fmoc chemistry. Gastrin receptor affinities were determined by receptor autoradiography using 125I-CCK as radioligand. To obtain information on secondary structure circular dichroism (CD) spectroscopy of natIn-labeled peptides was performed. Enzymatic stability was determined by incubating the 111In-labelled peptides in fresh human serum. Biodistribution studies were performed in AR4-2J-tumour-bearing Lewis rats. To reduce kidney uptake gelofusine was pre-injected in selected group of rats. Results. Both peptides showed high binding affinity to the gastrin receptor with IC50 values in nM range. CD measurements revealed difference in secondary structure of both peptides, in water, random coil conformation in case of (L-Glu)6 spacer analogue vs. type II reverse turn conformation in case of (D-Glu)6 spacer congener. The metabolic stability was 2.5-fold higher in case of (D-Glu)6 spacer analogue with T1/2 of (175 ± 71)h in comparison to (L-Glu)6 spacer analogue where T1/2 was determined to be (75 ± 23)h. Biodistribution study showed differences in tumour and kidney uptake. Tumour-to-kidney ratio was more than 10-fold better in case of (D-Glu)6 spacer congener at 4h p.i. and (1.1 vs. 0.1) and remaining better also after 24h p.i. (0.72 vs. 0.05). Surprisingly, gelofusine reduced kidney retention for different extent. In case of (D-Glu)6 spacer analogue just 2-fold reduction was observed while in case of (L-Glu)6 spacer analogue the kidney uptake was reduced 19-fold. Conclusion. Based on our results we can conclude that metabolic stability and high kidney retention of radiolabelled ionic-spacer minigastrin analogues are not determined solely by the charge of the ligand, but rather by the stereochemistry and secondary structure of the ligand.
Abstract The registration of a new PET radiopharmaceutical by medicines agencies is infrequent and it seemed interesting to follow its consequences on the prescription of alternative nuclear medicine (NM) examinations by the referring physicians. Fluorocholine (18F) (FCH) was registered in France for localisation of bone metastases of prostate cancer (PC) on April 2nd 2010. Methods A survey of the prescription of NM examinations in patients with PC was performed at Hôpital Tenon, covering eight quarters since the registration of FCH. Results During that period of time, 721 NM examinations were performed in PC patients. Demand for FCH PET/CT grew rapidly, from 11% of the NM examinations during the first quarter to 37% during the second quarter andto 56% during the eighth quarter. The total number of NM examinations requested for PC also grew over that period. Overall, the share of FCH PET/CT was 42%, 27% for bone PET/CT with fluoride (18F) (F Na), 25% for bone scintigraphy (BS). FDG PET/CT remained limited to few cases of castrate-resistant or metastatic PC (6% of NM examinations). Examinations limited to the detection of bone metastases (F Na and BS) were predominantly demanded for initial staging while FCH was more frequently requested in case of occult recurrence, at lower PSA serum levels. Therapy monitoring and follow-up appeared to be promising settings requiring assessment; 19% of NM examinations were prescribed in this context, same proportion as restaging prior to treatment resuming. Conclusion The introduction of FCH resulted in a rapid demand for this PET/CT examination, in particular in case of occult recurrence, with an overall increase in PC patients referred to NM imaging, of + 11% comparing the two successive years.
Functional imaging of prostate carcinoma is important especially for restagingof the disease in the case of biochemical relapse. The powerful imaging modality F-18 choline PET/CT (FCH PET/CT) improves assessment of clinically silent sites of recurrence. Despite rich vascularization and vascular communication between the penis and the prostate, metastatic involvement of the penis is relatively infrequent. We present a prostate cancer patient with unusual FCH uptake in a penile metastasis from prostate cancer. Metastasis from prostate adenocarcinoma to the bulbus and corpus of penis was identified with FCH during follow-up, 3 years after the initial diagnosis.