The use of peptides for the early detection and treatment of biological malignancies has had a profound effect on the field of molecular imaging. Due in part to their small size, rapid targeting, and relative ease to synthesize, peptides are ideal candidates for radiolabeling using short-lived isotopes such as 18F to provide in vivo visualization of the biomarker of interest using positron emission tomography (PET). The pioneering work of Bruce Merrifield to develop solid-phase peptide synthesis (SPPS) has facilitated the preparation of high-purity peptides and emerged as the methodology of choice for the rapid synthesis and site-specific radiolabeling of peptides for in vivo imaging. We have previously utilized this approach to synthesize and radiolabel the 20 amino acid peptide [18F]FBA-PEG2-A20FMDV2, a selective radiotracer derived from the foot and mouth disease virus (FMDV) that targets the cancer-related [alpha subscipt v][beta]6 integrin. Though this work demonstrated, among other benefits, the successful use of SPPS for the development of peptide-based molecular probes, it did not assess the affects of the solid support (resin) on crude peptide purity, radiochemical yields, and radiolabeling efficiency. Therefore, the aim of this work was to develop a generic platform that not only facilitates the selection of resins with optimal qualities for SPPS, but also identifies solid supports that can be utilized to facilitate the rapid, reliable construction of high-purity radiolabeled peptides for in vivo imaging with PET. To develop this platform, ten representative solid supports (resins) were chosen (amides n = 4, acids n = 3, alcohols n = 3) and analyzed based on several parameters including swelling capacity, SPPS performance, and radiochemical yields during 4-[18F]fluorobenzoic acid ([18F]FBA) conjugation. Resin swelling was independently assessed using common SPPS solvents and SPPS performance was analyzed by comparing the post-synthesis yields of the notoriously difficult control peptide Val-Glu-Ala-Ala-Ile-Asp-Tyr-Ile-Asn-Gly (VQAAIDYING) under standard coupling conditions (3 eq amino acid, 3 eq HATU, 6 eq DIPEA, 1.5 hr, r.t.). The control peptide was then radiolabeled with [18F]FBA on amide and acid resins by employing a.) standard solid-phase coupling conditions (5 mg HATU, 10 [microliter] DIPEA, 30 min, r.t.) b.) heated reaction conditions (5 mg HATU, 10 [microliter] DIPEA, 30 min, 37°C) and c.) reduced coupling reagent equivalents (1.5-10 eq HATU, 3-44 eq DIPEA, 30 min, r.t.) in efforts to determine optimal solid-phase radiolabeling conditions and evaluate radiochemical yields and radiolabeling efficiency. Optimized conditions were tested through the synthesis of [18F]FBA-PEGA28-20FMDV2, a biologically relevant peptide which selectively targets the [alpha subscipt v][beta]6 integrin in vivo. Resins comprised exclusively of the polyethylene glycol polyacrylamide (PEGA) copolymer matrix exhibited the greatest swelling capacity and produced peptides with excellent purities (>87% ± 5.8%). Novasyn TGR, consisting of a polystyrene (PS) backbone cross-linked with polyethylene glycol (PEG), displayed poor swelling yet produced crude products with purities of 97.0 ± 2%. We also observed that Novasyn TGR exhibited the highest radiolabeling efficiency (86.1 ± 0.84%) between post-[18F]FBA conjugation and post-cleavage radiochemical yields, whereas the PEGA resins produced low radiochemical yields post-cleavage, which led to poor efficiencies (42.7 ± 0.96% Rink Amide PEGA, and 42.4 ± 0.86% HMPA PEGA). Heated [18F]FBA conjugation reactions enhanced efficiencies by 15.4% (Rink Amide PEGA) and by 25.9% (HMPA PEGA) while heated cleavage reactions increased efficiencies by 14.0% (Rink Amide PEGA) and 48.7% (HMPA PEGA). Additionally, reduction of the coupling reagent equivalents (6 eq HATU, 23 eq DIPEA) used during [18F]FBA conjugation improved efficiencies by 17.5% and 24.9% for Rink Amide PEGA and HMPA PEGA, respectively. When applied during [18F]FBA radiolabeling of the PEG28-A20FMDV2 peptide, the optimized conditions increased radiochemical yields by 23.2% on Rink Amide AM, 39.7% on Rink Amide PEGA, and by 131.8% on Novasyn TGR. This study successfully demonstrates the effects of solid supports during SPPS, in particular during [18F]FBA radiolabeling, and resulted in an optimized model for the synthesis of biologically relevant radiolabeled peptides in a reliable and efficient manner.