Treatment of patients with advanced medullary thyroid carcinoma (MTC) is still a challenge. For more than 2 decades it is known that cholecystokinine-2 receptor (CCK2R) is a promising target for the treatment of MTC with radiolabeled minigastrin analogues. Unfortunately, kidney toxicity precluded their therapeutic application so far. In 6 consecutive patients we evaluated with advanced 3D dosimetry whether improved minigastrin analogue 177 Lu-DOTA-(DGlu) 6-Ala-Tyr-Gly-Trp-Nle-Asp-PheNH 2 (177 Lu-PP-F11N) is a suitable agent for the treatment of MTC. Methods: Patients received two injections of about 1 GBq (~80 µg) 177 Lu-PP-F11N with and without a solution of succinylated gelatin (SG, a plasma expander used for nephroprotection) in a random cross-over sequence in order to evaluate biodistribution, pharmacokinetics as well as tumor-and organ dosimetry. Electrocardiogram, blood count and blood chemistry were measured up to 12 weeks after administration of 177 Lu-PP-F11N to assess safety. Results: In all patients 177 Lu-PP-F11N accumulation was visible in tumor tissue, stomach and kidneys. Altogether 13 tumors were eligible for dosimetry. The median (interquartile range = IQR) absorbed dose for tumors, stomach, kidneys and bone marrow was 0.88 Gy/GBq (0.

Patients with metastatic medullary thyroid cancer (MTC) have limited systemic treatment options. The use of radiolabeled gastrin analogs targeting the cholecystokinin-2 receptor (CCK2R) is an attractive approach. However, their therapeutic efficacy is presumably decreased by their enzymatic degradation in vivo. We aimed to investigate whether the chemically stabilized analog Lu-DOTA-PP-F11N (Lu-DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2) performs better than reference analogs with varying in vivo stability, namely Lu-DOTA-MG11 (Lu-DOTA-DGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2) and Lu-DOTA-PP-F11 (Lu-DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2), and if the use of protease inhibitors further improves CCKR2-targeting. First human data on Lu-DOTA-PP-F11N are also reported. In vitro stability of all analogs was assessed against a panel of extra- and intra-cellular endoproteases, while their in vitro evaluation was performed using the human MTC MZ-CRC-1 and the transfected A431-CCK2R(+) cell lines. Biodistribution without and with the protease inhibitors phosphoramidon (PA) and thiorphan (TO) was assessed 4h post-injection in MZ-CRC-1 and A431-CCK2R(+) dual xenografts. Autoradiography of Lu-DOTA-PP-F11N (without and with PA) and nanoSPECT/CT images were performed. SPECT/CT images ofLu-DOTA-PP-F11N in a metastatic MTC patient were also acquired. natLu-DOTA-PP-F11N is less of a substrate for neprilysines than the other analogs, while intracellular cysteine proteases, like cathepsins-L, might be involved in the degradation of gastrin analogs. The uptake of all radiotracers was higher in MZ-CRC-1 tumors, compared to A431-CCK2R(+), apparently due to the higher number of binding sites on MZ-CRC-1 cells.Lu-DOTA-PP-F11N has the same biodistribution as Lu-DOTA-PP-F11, however, the uptake in the MZ-CRC-1 tumors is almost double (20.7±1.71 vs 11.2±2.94 %IA/g, = 0.0002). Co-administration of PA or TO increases significantly the Lu-DOTA-MG11 uptake in the CCK2R(+) tumors and stomach. Less profound is the effect onLu-DOTA-PP-F11, while no influence or even reduction is observed for Lu-DOTA-PP-F11N (20.7±1.71 vs 15.6±3.80 (with PA) %IA/g, p<0.05 in MZ-CRC-1 tumors). First clinical data show high Lu-DOTA-PP-F11N accumulation in the tumors, stomach, kidneys and colon. The performance of Lu-DOTA-PP-F11N without protease inhibitors is as good as the performance ofLu-DOTA-MG11 in the presence of inhibitors. The human application of single compounds without unessential additives is preferable. Preliminary clinical data spotlight stomach as a potential dose-limiting organ beside the kidneys.

The production of novel radionuclides is the first step towards the development of new effective radiopharmaceuticals, and the quality thereof directly affects the preclinical and clinical phases. In this review, novel radiometal production for medical applications is briefly elucidated. The production status of the imaging nuclide 44Sc and the therapeutic β--emitter nuclide 161Tb are compared to their more established counterparts, 68Ga and 177Lu according to their targetry, irradiation process, radiochemistry, and quality control aspects. The detailed discussion of these significant issues will help towards the future introduction of these promising radionuclides into drug manufacture for clinical application under Good Manufacturing Practice (GMP).

Brain uptake of [F]PSS232 matched the distribution of mGlu and followed a two-tissue compartment model. The well-defined kinetics and the possibility to use reference tissue models, obviating the need for arterial blood sampling, make [F]PSS232 a promising fluorine-18 labeled radioligand for measuring mGlu density in humans.