Background <p>Neuroendocrine neoplasms (NENs) represent heterogeneous tumors with increasing occurrence rate. Somatostatin receptor (SSTR) imaging using ⁶⁸Ga-labeled analogs is crucial but limited by the relatively short half-life of this radionuclide along with its reliance on generator supply. To overcome these limitations, this study aimed to establish an automated synthesis platform compliant with Good Manufacturing Practice (GMP) standards for the preparation of a novel SSTR-targeting probe, [¹⁸F]AlF-NOTA-octreotide. Its diagnostic efficacy in neuroendocrine neoplasms was evaluated through comparison with existing ⁶⁸Ga-labeled and [¹⁸F]FDG probes.</p> Results <p>The fully automated-synthesis of [¹⁸F]AlF-NOTA-Octreotide was completed within 37 minutes, with a specific activity of 56 ± 5 GBq/μmol and a radiochemical yield (RCY) of 42 ± 1.5%. The RCP was &gt; 95% and remained stable for 8 hours at room temperature. The [⁶⁸Ga]Ga-NOTA-Octreotide kit demonstrated an RCP of 97.5 ± 0.3%, stability ≥94% for 4 hours, and long-term stability ≥ 96% over 6 months. In vivo imaging in mice showed comparable tumor uptake for both probes at 30 minutes post-injection (5.6 %ID/cc). However, [¹⁸F]AlF-NOTA-Octreotide exhibited significantly lower background activity in blood, muscle, and bone. The tumor uptake of [¹⁸F]AlF-NOTA-Octreotide remained high (5.92 ± 0.10 %ID/cc) at 2 hours post-injection, superior to that of the ⁶⁸Ga-labeled counterpart (5.05 ± 0.68 %ID/cc). At the patient level, [¹⁸F]AlF-NOTA-Octreotide detected 41 (87.2%) among 47 lesions, whereas [¹⁸F]FDG detected only 13 (27.7%). For G1-G2 grade lesions, the SUVmax was significantly higher with [¹⁸F]AlF-NOTA-Octreotide compared to [¹⁸F]FDG (14.9 ± 13.8 to 4.8 ± 4.4, <i>p</i> &lt; 0.001). [¹⁸F]AlF-NOTA-Octreotide demonstrated superior detection of primary tumors, lymph node metastases, hepatic, osseous, and peritoneal metastases compared to FDG. One case of pulmonary atypical carcinoid (G3) was FDG-positive but Octreotide-negative, illustrating the complementary nature of the two imaging modalities.</p> Conclusions <p>A robust, GMP-compatible automated synthesis process for [¹⁸F]AlF-NOTA-Octreotide and a lyophilized kit for [⁶⁸Ga]Ga-NOTA-Octreotide were successfully established, both exhibiting high RCP, high specific activity, and excellent stability. [¹⁸F]AlF-NOTA-Octreotide demonstrated significantly higher lesion detection rates and uptake intensity than [¹⁸F]FDG in SSTR2-positive NENs with lower background activity. The complementary profiles of these probes enable personalized, precise imaging based on tumor biology. This work provides substantial technical and data support for clinical translation.</p>