Clinical performance of [99mTc]Tc-HYNIC-PSMA-XL-2 SPECT/CT in prostate cancer: paired head-to-head comparisons with [99mTc]Tc-MDP and PSMA PET/CT.

PURPOSE: [99mTc]Tc-HYNIC-PSMA-XL-2 is a PSMA-targeted SPECT tracer with low urinary bladder activity. We assessed its real-world performance in paired head-to-head comparisons versus [99mTc]Tc-MDP and PSMA PET/CT. METHODS: Single-center retrospective study (Jan 1, 2020–Nov 25, 2025) using within-patient paired scans within 30 days. Subcohort A included [99mTc]Tc-HYNIC-PSMA-XL-2 SPECT/CT vs. [99mTc]Tc-MDP (n = 38). Subcohort B included [99mTc]Tc-HYNIC-PSMA-XL-2 SPECT/CT vs. PSMA PET/CT (either [68Ga]Ga-PSMA-11 or [18F]PSMA-1007; n = 13). Lesions were classified by a composite reference standard (Gold+/Gold−). Sensitivity/specificity/accuracy were compared with McNemar’s test; non-inferiority versus PET/CT used Δ = 10% (sensitivity and accuracy). RESULTS: In Subcohort A, 76 bone lesions were evaluated (Gold + 60, Gold − 16). Sensitivity was high for both modalities (MDP 100.0% vs. [99mTc]Tc-HYNIC-PSMA-XL-2 98.3%; P = 1.000). [99mTc]Tc-HYNIC-PSMA-XL-2 showed higher specificity (100.0% vs. 18.8%; P < 0.001) and accuracy (98.7% vs. 82.9%; P < 0.001), with fewer false positives (FP 0 vs. 13). In Subcohort B, overall lesion sensitivity was comparable (93.1% vs. 96.6%; P = 1.000), and non-inferiority criteria were met (Δ = 10%); specificity estimates were limited by few Gold− lesions. CONCLUSION: [99mTc]Tc-HYNIC-PSMA-XL-2 SPECT/CT reduces false-positive bone findings versus [99mTc]Tc-MDP and meets prespecified non-inferiority criteria versus PSMA PET/CT, supporting its potential as an accessible PSMA imaging option.